Relevance of nutritional assessment and treatment to counteract cardiac cachexia and sarcopenia in chronic heart failure

Narrative Review Relevance of nutritional assessment and treatment to counteract cardiac cachexia and sarcopenia in chronic heart failure Antía Fern andez-Pombo a , 1 , Gemma Rodríguez-Carnero a , b , 1 , Ana I. Castro a , c , Ana Cant on-Blanco a , b , c , Luisa M. Seoane c , d , Felipe F. Casanueva c , e , f , Ana B. Crujeiras b , c , * , Miguel A. Martínez-Olmos a , b , c , f , ** a Division of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain b Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigaci on Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain c CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Madrid, Spain d Endocrine Physiopathology Group, Instituto de Investigaci on Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain e Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigaci on Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), Santiago de Compostela, Spain f Universidade de Santiago de Compostela, Santiago de Compostela, Spain article info Article history: Received 15 April 2021 Accepted 21 July 2021 Keywords: Cardiac cachexia Sarcopenia Chronic heart failure Muscle wasting Malnutrition summary Chronic heart failure (CHF) is frequently associated with the involuntary loss of body weight and muscle wasting, which can determine the course of the disease and its prognosis. While there is no gold standard malnutrition screening tool for their detection in the CHF population, several bioelectrical and imaging methods have been used to assess body composition in these patients (such as Dual Energy X- Ray Absorptiometry and muscle ultrasound, among other techniques). In addition, numerous nutritional biomarkers have been found to be useful in the determination of the nutritional status. Nutritional considerations include the slow and progressive supply of nutrients, avoiding high volumes, which could ultimately lead to refeeding syndrome and worsen the clinical picture. If oral feeding is insufficient, hypercaloric and hyperproteic supplementation should be considered. b -Hydroxy- b -methylbutyrate and omega-3 polyunsaturated fatty acid administration prove to be beneficial in certain patients with CHF, and several interventional studies with micronutrient supplementation have also described their possible role in these subjects. Taking into account that CHF is sometimes associated with gastrointestinal dysfunction, parenteral nutritional support may be required in selected cases. In addition, potential therapeutic options regarding nutritional state and muscle wasting have also been tested in clinical studies. This review summarises the scientific evidence that demonstrates the necessity to carry out a careful nutritional evaluation and nutritional treatment to prevent or improve cardiac cachexia and sarcopenia in CHF, as well as improve its course. ©2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction Chronic heart failure (CHF) is a complex clinical condition that represents the final evolution of several cardiovascular diseases and has a tremendous economic impact on public health systems. Recent data show that around 26 million people worldwide suffer from CHF [1] and, in developed countries, it has a prevalence of 1e2% in the general population [1,2]. Involuntary loss of body weight and muscle wasting are common in the CHF population, particularly in more advanced disease *Corresponding author. Instituto de Investigaci on Sanitaria, Complejo Hospitalario Universitario de Santiago (CHUS), C/Choupana, s/n, 15706, Santiago de Compostela, Spain. ** Corresponding author. Instituto de Investigaci on Sanitaria, Complejo Hospitalario Universitario de Santiago (CHUS), C/ Choupana, s/n, 15706, Santiago de Compostela, Spain. E-mail addresses: [email protected] (A.B. Crujeiras), miguel.angel. [email protected],[email protected] (M.A. Martínez-Olmos). 1 These authors contributed equally to this manuscript. Contents lists available at ScienceDirect Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu https://doi.org/10.1016/j.clnu.2021.07.027 0261-5614/©2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical Nutrition 40 (2021) 5141e5155 states. An incidence of severe malnutrition is estimated at 7.5% and moderate in 57% of patients [3], with an increase in mortality of 2e10 times more than in patients with CHF without malnutrition [4]. Despite promising advances in the management of drugs and new devices in the last decade, patients with CHF remain at significantly higher risk of morbidity and mortality than the general population [5]. Therefore, attention in recent years has increasingly turned to additional substrates that may positively impact CHF outcomes, unlike the traditional models of the cardiovascular system, including associated metabolic and wasting conditions [6]. It is known that the early identification and treatment of malnutrition may be associated with better outcomes in this group of patients, including those who may need advanced therapies such as ventricular assist devices (LVAD) and heart transplantation [7]. For this reason, as stated in previous reviews [8e17], nutritional assessment and treatment are finding an increasingly important place in clinical practice. However, there are no specific detailed recommendations on nutritional evaluation and management of patients with CHF in the current nutritional guidelines. Therefore, this review aims to gather the most relevant scientific evidence in this field, as well as point out possible gaps in the nutritional assessment and treatment of patients with cardiac cachexia or sarcopenia while proposing future research in this specific population. 2. Pathophysiological mechanisms leading to malnutrition in chronic heart failure CHF and impaired nutritional status and muscle wasting share many common pathophysiological processes (Fig. 1). HF symptoms such as dyspnoea may consume a significant amount of energy and lead to anorexia and swallowing disturbances. Restricted diets and polimedication in these patients contribute to the development of these alterations. Gut oedema, hepatic congestion and intestinal hypoperfusion may result in early satiety, nausea and therefore anorexia, as well as nutrient malabsorption [18]. Impaired cardiac pump function also induces a systemic response characterised by neurohormonal and inflammatory activation, which are initially beneficial as they induce cytoprotective responses, although both become maladaptive over time [8]. An additional imbalance between anabolic and catabolic metabolism in these patients results in a reduction in anabolic mediators, including growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, and ghrelin, as well as an increase in inflammatory mediators such as tumour necrosis factor alpha (TNF- a ), interleukin-6 (IL-6) and C-reactive protein (CRP) with the consequent increase in oxidative stress [4,7]. Furthermore, comorbidities are extremely common in CHF and have an important influence on the clinical course of the disease and on patient outcomes, making them more vulnerable to nutritional deficiencies. These comorbidities include, in addition to coronary artery disease and hypertension, chronic obstructive pulmonary disease, chronic kidney disease, diabetes mellitus and anaemia, among others [19]. This combination of inadequate protein intake, nutrient malabsorption, catabolic processes, inadequate anabolism, physical inactivity and the possible associated comorbidities can eventually lead to cachexia and sarcopenia. The term cachexia has been defined as involuntary weight loss 5e6% over at least 6 months, in the absence of oedema, compared to the normal premorbid weight [20,21]. A prevalence of 5%e15% is estimated [22,23], and its prognosis is dire, with mortality rates 2e3 times higher compared to patients with non-cachectic CHF [9,22,23]. On the contrary, sarcopenia has classically been defined as the loss of skeletal muscle mass and strength in parallel with the preservation of fat mass (FM) [24], unlike cachexia, in which a reduction in FM is observed [10]. Its prevalence in patients with CHF is 20% [25], and it is associated with a greater severity of the disease and can predict long-term survival [26]. It has been shown that in patients undergoing LVAD implantation or after cardiac transplantation, sarcopenia, as measured by Fig. 1. Main pathophysiological alterations that occur in the development of malnutrition in relation to heart failure. GH: growth hormone; IGF-1: insulin-like growth factor-1; TNF- a : tumour necrosis factor alpha; CRP: C-reactive protein; IL-6: interleukin-6; RAAS: renineangiotensinealdosterone system; SNS: sympathetic nervous system. A. Fern andez-Pombo, G. Rodríguez-Carnero, A.I. Castro et al. Clinical Nutrition 40 (2021) 5141e5155 5142 psoas muscle area, is associated with major morbidity and increased mortality [27,28]. However, it is not clear whether reduced muscle strength is a mediator or simply a marker of worse nutritional status related to a greater risk of cardiometabolic diseases [29]. Thus, current evidence suggests that CHF is associated with alterations in energy metabolism at the myocardial level, which influences the nutritional state. Therefore, nutritional intake represents a fundamental component in the evolution of the disease. 3. Nutritional screening Different screening tools have been used in patients with CHF. However, none of them has been postulated as the gold standard. Therefore, any of those available are valid (Nutritional Risk Screening 2002 [NRS 2002], Subjective Global Assessment [SGA], Mini Nutritional Assessment [MNA], Malnutrition Universal Screening Tool [MUST], Short Nutritional Assessment Questionnaire [SNAQ]), always taking into account the setting in which they are performed (hospitalised, outpatient or elderly patient) [30e34]. Regarding MNA, in a study conducted on 130 ambulatory patients with CHF, recruited as a part of the SICA-HF programme, its short form (MNA-SF) was shown to be an independent predictor of muscle wasting and mortality [35]. In addition, the SARC-F is a simple 5-item screening test for sarcopenia [36]. Although it was found to have high specificity, its major weakness is its low sensitivity. Subsequently, it has been reported that adding calf circumference to the SARC-F (SARC-calF test) could significantly improve the sensitivity of this test [37]. Another quick 5-question test is the Mini Sarcopenia Risk Assessment (MSRA), which also has superior sensitivity in the detection of sarcopenia than the SARC-F [38]. For critically ill patients (which may include those with cardiogenic shock), the American Society for Parenteral and Enteral Nutrition (ASPEN) recommends, in addition to NRS 2002, the use of the Nutrition Risk in the Critically ill (NUTRIC) score [39], unlike the European Society for Clinical Nutrition and Metabolism (ESPEN) [40]. For the diagnosis of malnutrition, the newer consensus scheme from the Global Leadership Initiative on Malnutrition (GLIM) has also been proposed on a global scale [41], which may be predictive of refeeding syndrome (RS) [42]. However, none of these previously mentioned tools have been specifically validated in the CHF population for risk screening or diagnosis of malnutrition. 4. Anthropometry and body composition evaluation It is reasonable that, in patients with CHF, an annual weight assessment should be carried out due to the strong association between cachexia and adverse clinical outcomes. However, the evaluation of malnutrition in patients with CHF is complicated considering that the underlying loss of muscle mass and weight may be masked by oedema. Thus, it should be borne in mind that in routine clinical evaluations the weight and body mass index (BMI) of the patient in question may remain stable in the context of congestion when the patient is actually malnourished. In fact, in patients with CHF and either reduced or preserved left ventricular systolic function, low BMI was associated with increased mortality, but this only occurred in subjects without oedema [43]. Handgrip strength measured by dynamometry has been used as an isolated surrogate marker for muscle strength and frailty [29], and it has been associated with higher postoperative complication rates and increased mortality in patients with advanced CHF undergoing LVAD implantation [44]. There are also numerous bioelectrical and imaging methods that have been used to assess body composition indirectly in the context of CHF, including bioelectrical impedance analysis (BIA), Dual Energy X-Ray Absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI) and muscle ultrasound. BIA is a fast, safe, inexpensive and easy-to-use option that provides an estimate of body composition based on mathematical calculations. It requires validation in the study population and also has limited use in patients with alterations in hydration [24,45,46]. This issue can be overcome by using bioelectrical impedance vector analysis (BIVA), which brings vectors inside the impedance target in clinical conditions of altered body hydration, independently of body weight [45,47]. On the other hand, DXA (Fig. 2) has recently been defined as the gold standard and an easy-to-use method, with minimal exposure to radiation, and a lower cost than CT or MRI [48]. However, inter-individual and intra-individual changes in body water make it an unreliable tool in patients with CHF [49]. CT and MRI of the pectoral muscle, psoas, or quadriceps can be considered alternative approaches to calculate FM and fat-free mass (FFM), providing reproducible and reliable images. Nevertheless, they are expensive techniques, are available only in major medical centres, require highly-trained personnel, and have some operative contraindications [24,50e52]. Finally, as far as muscle ultrasound (Fig. 2) is concerned, it is postulated as a muscle mass measurement technique of the future due to its simplicity, low cost, availability and good correlation with the data obtained by MRI. However, at present it is not completely standardised and cut-offs for low muscle mass are not universally defined [53]. 5. Nutritional biomarkers The values of some biochemical parameters have been studied as possible markers of nutritional status in patients with CHF. Serum visceral proteins such as albumin (half-life of 14e21 days) and prealbumin (half-life of 2e3 days), have traditionally been used. Albumin has been identified as a useful indicator of adverse prognosis in patients with advanced CHF and in patients undergoing LVAD implantation. Its levels can also be correlated with the degree of frailty identified by low handgrip strength in this group [44]. Given its role as a negative acute phase reactant, its synthesis is suppressed in inflammatory settings. Therefore, it should be considered in combination with C-reactive protein (CRP) evaluation [54]. On the other hand, prealbumin is less sensitive to hydration status and, for this reason, it is recognised as a better marker of protein malnutrition. It is also a negative acute phase reactant, but although CRP must also be considered, unlike albumin, it can be used to monitor changes in the same patient. Furthermore, prealbumin levels have been associated with mortality and higher readmission rates in patients with acute HF [7,55]. In addition to albumin and prealbumin, laboratory abnormalities commonly associated with malnutrition, including low total cholesterol, lymphopenia and anaemia, have been evaluated in patients with CHF and related with unintentional weight loss of 7.5% in this population. Low total cholesterol was also associated with worse outcomes [56]. Furthermore, there are other biochemical parameters which have been considered to be possible modern biomarkers of nutritional status, such as ghrelin, leptin, adiponectin, myostatin or growth differentiation factor 8 (GDF-8) and the C-terminal agrin fragment (CAF). As far as ghrelin is concerned, its levels have been reported to be elevated in patients with HF and cardiac cachexia in comparison with those with only HF [57]. At the same time, it inhibits the release of leptin, which has also been proved to be lower in cachectic CHF patients compared with noncachectic subjects [58]. Adiponectin is elevated in cardiac cachexia and is correlated positively with weight loss and Brain Natriuretic Peptide (BNP) [59]. In addition, an increase in mortality risk has been observed in CHF patients with adiponectin levels above the average [60]. GDF-8 is a protein found mainly in A. Fern andez-Pombo, G. Rodríguez-Carnero, A.I. Castro et al. Clinical Nutrition 40 (2021) 5141e5155 5143 skeletal muscle and characterised by inhibiting its growth [61]. It seems to be up-regulated in animal models with volume-overload HF [62]. Finally, CAF, produced by the enzyme neurotrypsin, has been investigated as a potential biomarker of muscle wasting. Thus, in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF), patients with muscle wasting identified by DXA had higher levels of CAF [7,63]. In addition to the previously mentioned biochemical parameters, the inflammatory markers interleukin-1 (IL-1), IL-6, CRP, and tumour necrosis factor alpha (TNF- a ) may also be significantly elevated in patients with CHF, particularly those suffering from cachexia and sarcopenia [58,64,65]. Increased levels of these parameters have been associated with low handgrip strength in people over 65 years of age and with higher mortality in patients with CHF [66,67]. On the other hand, the GH/IGF-1 axis also has multiple effects on cardiac function, such as the regulation of cardiac growth, stimulation of myocardial contractility and reduction of vascular resistance [68]. Abnormalities in GH/IGF-1 have been identified in cachectic patients with CHF, presenting features of acquired GH resistance [69]. However, there is no consensus on the best way to biochemically evaluate the GH/IGF-1 axis. Thus, its use as a biomarker in CHF is currently limited. Likewise, low levels of testosterone have been described in 22e39% of men with CHF [70e72]. These low levels are associated with loss of muscle mass and decreased survival, as well as serving as an independent predictor of exercise intolerance according to the reduction in peak oxygen consumption (VO 2 )[70,73]. 6. Dietary recommendations and nutritional support For a long time, the therapeutic approach has focused only on the myocardium and the cardiovascular system itself. However, other approaches focused on metabolism and nutrition are increasingly being sought as current and future targets for new successful therapies [6]. Nevertheless, there are no comprehensive dietary counselling guidelines for patients with CHF or large trials that have investigated whether dietary interventions can correct cachexia or sarcopenia in CHF. It is possible that simply increasing protein-calorie intake, for example, by adopting the PROT-AGE protein targets (a target protein intake of 1.0e1.2 g/kg/day) [74], may be insufficient to overcome the muscle wasting process [11]. However, the Nutritional Intervention Program in Malnourished Patients Admitted for Heart Failure (PICNIC) established that individualised nutritional intervention during and after admission due to acute HF may have a prognostic benefit[75]. This multicentre clinical trial included 120 malnourished hospitalised patients with acute HF, who were randomised to conventional treatment or nutritional intervention (diet optimisation, specificrecommendations and nutritional supplement prescriptions if necessary). At the end of the study, the composite endpoint of all-cause mortality or readmission for worsening of HF occurred in 27.1% of patients in the intervention group and in 60.7% of patients in the control group (hazard ratio 0.45; 95% CI 0.19e0.62, p ¼0.0004) [75]. However, clinical trials validating specific cachexia and sarcopenia interventions in other CHF populations will be needed to formulate future clinical recommendations. As general recommendations, in patients with CHF associated or not with cardiac cachexia, it has been suggested to start feeding with a low kcal/kg ratio, with a slow and progressive supply of nutrients and avoiding high volumes with low energy density [76]. If necessary, oral or enteral supplementation should represent the first option when patients with cardiovascular disease require nutritional support. However, CHF is sometimes associated with changes in intestinal morphology, permeability, and absorption Fig. 2. Comparative body composition determined by Dual-Energy X-Ray Absorptiometry and skeletal muscle ultrasound. Comparative, colour mapped, total body composition scans via whole-body Dual-Energy X-Ray Absorptiometry (A) of a 78-year-old subject with normal weight (A1), a 79-year-old subject with sarcopenic obesity (A2) and a 79-year-old subject with CHF and cardiac cachexia (A3). Green represents an area of low level % fat (0e25%), yellow an area of medium level % fat (25e60%), and red an area of high level % fat (60e100%). Fig. B corresponds to the skeletal muscle ultrasound of subject A3. Distance 1 represents the subcutaneous adipose tissue thickness, which is reduced, and distances 2 and 3 the rectus femoris muscle thickness in the y and x axes, respectively. Low muscle tone can be observed in this patient. The cross-sectional area of rectus femoris is also reduced. BMI: body mass index; FM: fat mass; FFM: fat-free mass. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) A. Fern andez-Pombo, G. Rodríguez-Carnero, A.I. Castro et al. Clinical Nutrition 40 (2021) 5141e5155 5144 [18], which must always be taken into account in case parenteral nutritional support is required. 6.1. Calculation of nutritional requirements As in the general population, the calculation of nutritional requirements can be made using several equations, such as the HarriseBenedict equation [77]. However, a number of considerations should be taken into account. In general, in healthy individuals, total energy expenditure (EE) is the sum of resting energy expenditure (REE) and physical activity-induced energy expenditure (AEE). Compared with healthy subjects, in CHF patients without cachexia, REE is initially increased due to hypermetabolism (increase in REE of approximately 10%), probably the first step towards weight loss. Later, once cachexia has developed, the REE falls below the value of healthy people. This is due to the fact that, at the same time, physical activity is very limited, thereby reducing energy expenditure (EE). Therefore, daily EE is reduced by 25% compared to healthy subjects and 20% compared to CHF patients without cachexia [78,79]. Regarding the distribution of macronutrients, the energy intake has to be adjusted to the nutritional status of the patient. It has been proposed that 22e30 kcal/kg of real weight is a good way to start the nutritional support in subjects with CHF [76] and, as far as protein distribution is concerned, the contribution must be individualised depending on the case, but generally 1.1 g/kg of body weight [61,80]. 6.2. Dietary strategies To avoid the sensation of dyspnoea while eating, it has been advised to recommend a soft diet as well as the distribution of several servings throughout the day [76]. Regarding the recommended dietary patterns, there is currently no evidence that the loss of muscle mass and strength can be reversed through changes in diet pattern. In this sense, in people with CHF or at risk of developing it, most societies support the adoption of a Mediterranean-style diet (MedDiet) or dietary approaches such as the Dietary Approaches to Stop Hypertension (DASH diet) [11]. Thus, the benefits of MedDiet probably lie in the fact that it is a dietary pattern rich in nutrients with anti-inflammatory properties such as the unsaturated fatty acids present in extra virgin olive oil, nuts and fish. Inflammation is known to be a shared feature of CHF and sarcopenia. For this reason, it has been postulated that this may be one of the mechanisms of the beneficial effect of MedDiet in CHF [81]. Furthermore, in the Prevenci on con Dieta Mediterr anea (PREDIMED) study, MedDiet was recognised as providing protection against the development of cardiovascular diseases [82,83] and, although there are currently diverse results on its ability to reduce the risk of CHF, recent research has shown that greater adherence to this type of diet can reduce hospital readmissions for this reason [84,85]. On the other hand, regarding the DASH diet, small clinical trials in patients with hypertensive CHF with preserved ejection fraction have shown a reduction in blood pressure, arterial stiffness, oxidative stress and an improvement in left ventricular diastolic function [86,87]. It has also been associated with fewer readmissions after hospitalisation due HF [88] and lower mortality [89]. Regarding sodium intake specifically, the European Society of Cardiology (ESC) postulates that in patients with CHF, excessive salt intake (>6 g/day) should be avoided [2]. Thus, for decades, dietary sodium restriction has been the cornerstone of CHF management alongside medical therapy. However, the data to support this recommendation is scarce, leading to inconsistent conclusions across professional societies. In addition, although some studies have shown benefits with sodium restriction [90,91], others have reported better results with sodium liberalisation [92,93]. 6.3. Oral nutritional supplementation When oral feeding is insufficient, oral nutritional supplementation is indicated. Hypercaloric (1.5e2kcal/ml)and,if necessary, hyperproteic supplements are generally recommended, since they seem to improve inflammation status, quality of life and survival in CHF patients [12,94]. In this sense, in recent years several trials have been carried out using specific protein supplements with theoretical effects on muscle. In this way, b -hydroxy- b -methylbutyrate (HMB), a metabolite of the amino acid leucine, has been shown to increase muscle mass gain in older adults [95]. In one of these randomised clinical trials (the NOURISH study), the effects of adding a nutritional supplement with HMB compared to placebo have been analysed in 652 patients over 65 years of age classified as malnourished by SGA and hospitalised for cardiovascular and pulmonary events such as congestive HF. An improvement in nutritional status and a significant reduction in the risk of mortality were observed in the HMB group [96]. In a later analysis, oral supplementation with HMB also significantly improved handgrip strength in this group of patients [97]. In addition, the ESC guidelines state that omega-3 polyunsaturated fatty acid (PUFA) supplementation may be considered to reduce the risk of cardiovascular hospitalisation and death in patients with HF, with a level of evidence B recommendation, class IIb [2]takinginto account the results of the GISSI-HF trial. This trial randomised 955 patients to receive a daily dose of 1 g PUFA or placebo and showed that all-cause mortality and the combined end point of all-cause mortality or hospital admission for cardiovascular reasons were lower in the group receiving PUFA [12,98]. The American College of Cardiology and American Heart Association (ACC/AHA) guidelines also state that PUFA supplementation should be considered in these patients, with a level of evidence B recommendation, class IIa [99]. 6.4. Micronutrients Micronutrients, which include vitamins and trace elements, are essential components in a high-quality diet since they intervene as regulatory elements in the functions of cellular metabolism [100]. Although there are no general recommendations in the clinical practice guidelines, there are several outstanding studies that have described their possible role in patients with CHF (Table 1). However, conflicting evidence can be observed probably partly due to the heterogeneity of the different studies and, specifically, due to the variability of dose supplementation used. It would likewise be relevant, in future clinical studies, to reduce variability in the population investigated to allow generalisable results. Determining the nutritional baseline state and taking into account possible poor intestinal absorption may also offer more personalised support. In addition, the evidence of the effectiveness of micronutrient supplementation is limited by the evaluation of surrogate endpoints such as cardiac function, ejection fraction, exercise tolerance or quality of life, rather than focussing on the investigation of its possible role as a prognostic marker for significant primary endpoints in CHF. Thus, to date, it is only advised to replace detectable deficiencies [99]. A. Fern andez-Pombo, G. Rodríguez-Carnero, A.I. Castro et al. Clinical Nutrition 40 (2021) 5141e5155 5145 Table 1 Selected studies on the role of micronutrient supplementation in chronic heart failure. Therapy Dose Duration Patient population Clinical effects Ref. Vitamin D 2000 IU cholecalciferol þ500 mg calcium daily. 15 months 123 subjects with CHF (1:1 vs placebo þ500 mg calcium). -No changes in the survival rate. -No differences in the improvement of LVEF or LVEDD. [129] 100,000 IU of oral ergocalciferol at baseline and at 10 weeks. 5 months 105 subjects with CHF (1:1 vs placebo). -No changes in 6MWT. -Worsening of QoL. -Reduction in NT-proBNP. [130] 4000 IU of oral cholecalciferol daily. 6 months 23 elderly subjects with CHF (1:1 vs placebo). - Improvement in ejection fraction. [131] 4000 IU of oral cholecalciferol twice daily. 12 months 223 subjects with CHF (1:1 vs placebo). - No improvement in 6MWT. - Improvement in LVEF (þ6.07%). [132] 4000 IU of oral cholecalciferol daily. 36 months 400 subjects with CHF (1:1 vs placebo). - No differences in mortality. - Greater need of mechanical circulatory support implant. - Improvement in LVEF function (þ2.60%) in CHF subjects aged 50 years. [133,134] 4000 IU of oral cholecalciferol daily. 36 months þ36 months after vitamin D cessation 400 subjects with CHF (1:1 vs placebo). - Higher risk of hospitalisation and mechanical circulatory support implant during vitamin D supplementation, which disappeared after its discontinuation. [135] Vitamin E 335.6 mg (500 IU) RRR- a tocopherol, 2 capsules daily. 3 months 56 subjects with CHF (1:1 vs placebo). - No improvement in markers of oxidative stress. - No improvement in concentrations of ANP. - No improvement in QoL. [136] 400 mg daily. 4 weeks 20 subjects with CHF (1:1 vs placebo). - Reduction in oxidative stress and increase in antioxidant enzymes. [137] Vitamin B 1 Intravenous thiamine 200 mg daily for one week, followed by oral thiamine 20 mg daily. 7 weeks 30 subjects with CHF who had received furosemide 80 mg daily (1:1 vs placebo). - Improvement in LVEF by 22%. [138] Thiamine 300 mg daily. 4 weeks 9 subjects with CHF and diuretic treatment (1:1 vs placebo). - Increase in LVEF to 32.8%. [139] Oral thiamine mononitrate 200 mg daily. 6 months 69 subjects with CHF (1:1 vs placebo). - Greater LVEF in the placebo group. - No differences in Minnesota Living with Heart Failure score, 6MWT and NT-proBNP. [140] Vitamin B 12 3 mg pyridoxine, 0.8 mg folate and 0.5 mg cyanocobalamine daily. 6 weeks 14 elderly subjects with CHF and plasma homocysteine >15 m M (1:1 vs placebo). - Improvement in respiratory muscle strength. - No change in exercise capacity. [141] Vitamin C 2 g bolus injection of vitamin C and subsequent 50 mg/min infusion for 10 min, in addition to dobutamine. Immediately after dobutamine and vitamin C injection 19 subjects with CHF (10 of them treated with vitamin C). - Increase in the left ventricular contractility response to dobutamine. - Improvement in myocardial efficiency. [142] 25 mg/min of intra-arterial vitamin C over 10 min and 1 g of oral vitamin C twice daily in 10 of the subjects with CHF. 4 weeks 15 subjects with CHF and 8 healthy subjects (2:1 vs placebo). - Improvement in endothelium-mediated, flow-dependent dilation. [143] Coenzyme Q10 150 mg daily. 3 months 39 subjects with CHF (1:1 vs placebo). - Improvement in NYHA class. - Increase in 6MWT. - Increase in exercise time. [144] 60 mg U daily of Ultrasome™. 3 months 32 subjects with CHF awaiting heart transplantation (1:1 vs placebo). - Improvement in 6MWT. - Decrease in dyspnoea, NYHA class, nocturia and fatigue. - No changes in echocardiography parameters, ANP and TNF levels. [145] 2 mg/kg daily. 12 months 641 subjects with CHF (1:1 vs placebo). - Reduction in hospitalisation. - Reduction in episodes of pulmonary oedema or cardiac asthma. - Lower incidence of arrhythmias. [146] 100 mg 3 times daily. 4 months 420 subjects with CHF (1:1 vs placebo). - Lower risk of major adverse cardiovascular events, [147] A. Fern andez-Pombo, G. Rodríguez-Carnero, A.I. Castro et al. Clinical Nutrition 40 (2021) 5141e5155 5146 6.5. Enteral and parenteral nutrition There are no specific recommendations on enteral/parenteral nutrition routes focussing on patients with CHF in the current nutritional guidelines. However, in general terms, when oral nutritional support is insufficient, the introduction of artificial nutrition should be considered, using an enteral route if the gastrointestinal tract is intact and available. Administration should be carried out by choice with a nasoenteric tube and, in the event that microaspirations or gastric paresis are suspected, a distal position of the tube at the duodenal level is recommended [101]. It has been advised that infusion should be continuous for 24 h or cyclical day/night for as many hours as possible. As for the formula, a normocaloric or hypercaloric polymeric diet has been recommended [76]. It should also be taken into account that CHF can be accompanied by gut oedema, hepatic congestion and intestinal hypoperfusion, which can lead to early satiety, nausea and gastrointestinal dysmotility [18], and, therefore, to a greater susceptibility to developing gastrointestinal dysfunction and intolerance to enteral feeding. In this sense, it has been widely recommended to consider parenteral nutritional support when oral feeding is not sufficient and the digestive apparatus is not functioning after 3e5 days, if oral/enteral intake is expected to be below half of the energy requirement for more than one week, or there is evidence of malabsorption [102]. A low fluid intake is also advised [103]. Thus, the use of a central catheter is suggested, avoiding the peripheral line as far as possible, since it requires high volumes to guarantee a tolerable osmolarity for the peripheral vein. A recommended caloric intake of approximately 25 kcal/kg of body weight has been proposed, and the excessive administration of glucose should be avoided for two reasons: Firstly, in order to avoid lipogenesis, the increase in carbon dioxide and the subsequent increase in the respiratory quotient, and also to avoid secondary hyperglycaemia [76]. 6.6. Physical activity At present, it is known that not only nutritional support itself, but also physical activity, are the main treatment options to counteract the consequences of sarcopenia and cachexia in CHF [12]. Thus, physical exercise must be considered as a complement to nutritional therapy. Cardiac rehabilitation programmes in patients with CHF have been demonstrated to improve functional capacity, exercise Table 1 (continued) Therapy Dose Duration Patient population Clinical effects Ref. cardiovascular mortality, allcause mortality and incidence of hospital stays. - Improvement in NYHA class. - No changes in 6MWT and NT- proBNP levels. 100 mg 3 times daily. 1 month 30 subjects with CHF (15 in intervention group and 15 in control group). - No additional benefits in improving LV diastolic function in subjects with HFpEF. [148] Iron 200 mg of intravenous ferric carboxymaltose weekly until iron repletion and then every 4 weeks. 6 months 459 subjects with CHF (2:1 vs placebo). - Improvement in NYHA class. - Improvement in 6MWT. - Improvement in QoL. [149] 500-2000 mg of intravenous ferric carboxymaltose at baseline and week 6 in the therapy phase, followed by 500 mg in weeks 12, 24 and 36 in case of iron deficit. 13 months 304 subjects with CHF (1:1 vs placebo). - Increase in 6MWT. - Improvement in NYHA class and fatigue score. - Improvement in QoL. - Reduction in the risk of hospitalisation for worsening HF. [150] 150 mg of oral iron polysaccharide twice daily. 4 months 225 subjects with CHF (1:1 vs placebo). - No differences in peak VO 2 . - No differences in 6MWT. - No differences in NT-proBNP levels. - No differences in QoL. [151] Two treatment groups in addition to the placebo group: 200 mg of intravenous iron sucrose weekly for 5 weeks; 200 mg of oral ferrous sulphate 3 times daily for 8 weeks. 3 months 23 subjects with CHF (10 receiving intravenous iron, 7 oral iron and 6 placebo). - Increment in peak VO 2 in the intravenous iron group. No increment in the oral iron group. [152] Selenium 200 m g of selenium yeast daily. 3 months 53 subjects with CHF (1:1 vs placebo). - Reduction in serum insulin and HOMA-IR. - Improvement in plasma lipid profile. [153] Multiple micronutrients a 250 mg, 150 mg, 15 mg, 1.2 mg, 50 m g, 800 m g, 200 mg, 2 mg, 200 mg, 5 mg, 200 m g, 500 mg, 400 mg, 10 m g, 150 mg, respectively. a 9 months 30 elderly subjects with CHF (1:1 vs placebo). - Reduction in left ventricular volume (13.1%). - Increase in LVEF by 5.3 ±1.4%. - Improvement in QoL score. - No changes in 6MWT. [154] LVEF: left ventricular ejection fraction; LVEDD: left ventricular end-diastolic diameter; ANP: atrial natriuretic peptide; QoL: quality of life; 6MWT: 6-min walk test; NT- proBNP: N-terminal Pro-B type natriuretic peptide; NYHA: New York Heart Association; TNF: tumour necrosis factor. a Calcium, magnesium, zinc, copper, selenium, vitamin A, thiamine, riboflavin, vitamin B 6 , folate, vitamin B 12 , vitamin C, vitamin E, vitamin D, and Coenzyme Q10. A. Fern andez-Pombo, G. Rodríguez-Carnero, A.I. Castro et al. Clinical Nutrition 40 (2021) 5141e5155 5147 Table 2 Studies of drugs with potential nutritional impact in patients with heart failure. Therapy Dose Duration Patient population Clinical effects Ref. Beta-blockers Carvedilol and metoprolol Carvedilol (target dose 25 mg twice daily), long-acting metoprolol succinate (target dose 200 mg daily). 6 months 27 subjects with CHF (13 cachectic vs. 14 non-cachectic). - Greater weight gain. - Greater increase in plasma leptin levels. - Greater decrease in plasma norepinephrine levels. [155] Carvedilol, bisoprolol and metoprolol Mean target dose: carvedilol (41.6 ±14.0 mg daily), bisoprolol (9.2 ±2.5 mg daily), metoprolol tartrate (200 mg daily). 8.7 ±3.5 months 41 non-cachectic CHF subjects. - Increase in total body fat mass and total body fat content. [156] Carvedilol Target dose 25 mg twice daily. 29 months 2289 subjects with CHF (1:1 vs placebo). - Reduction in the risk of weight loss >6% by 33%. [157] ACE inhibitors and ARB Enalapril 20 mg daily. 35 months 1929 subjects with CHF. - 19% reduction in the risk of weight loss of 6% or more. [23] Enalapril Losartan Enalapril (20 mg daily), losartan (50 mg daily). 6 months 16 male subjects with CHF (8 with enalapril and 8 with losartan). - Improvement in exercise capacity. - Increase in peak VO 2 . [158] ARNI-ARB Sacubitril/valsartan 46% 24/26 mg, 39% 49/51 mg, 15% 97/103 mg. 7.5 ±0.9 months 164 subjects with CHF. The switch from ACE inhibitors/ ARB to ARNI-ARB resulted in: - Decrease in the % of malnourished patients according to CONUT, GNRI and PNI scores. - Increase in prealbumin levels. - No change in body weight and BMI. [159] b 2 -Agonists Salbutamol 8 mg twice daily. 3 weeks 12 male subjects with CHF (1:1 vs placebo). - Improvement in respiratory muscle strength. - No change in exercise capacity. [160] Clenbuterol Target dose 40 m g twice daily. 3 months 19 subjects with CHF (1:1 vs placebo). - Increase in lean mass. - Decrease in exercise duration. - No change in peak VO 2 . [161] Ghrelin 2 m g/kg iv twice daily. 3 weeks 18 subjects with CHF (10 in the ghrelin group and 8 in the control group). - Increase in food intake. - Increase in muscle strength, lean body mass and left ventricular mass. - Increase in absolute peak VO 2 . - Decrease in plasma norepinephrine. [162] Testosterone 1000 mg of intramuscular longacting testosteroneundecanoate every 6 weeks. 3 months 70 elderly male subjects with CHF (1:1 vs placebo). - Improvement in the distance walked in the 6MWT. - Increase in peak VO 2 . - Improvement in insulin sensitivity. - Increase in body weight and BMI. [163] Intramuscular testosterone every 2 weeks. 3 months 20 male subjects with CHF (1:1 vs placebo). - Increase in the distance walked in the SWT. - No effect on skeletal muscle bulk, strength or weight. [164] 5 mg daily, transdermal. 12 months 76 male subjects with CHF (1:1 vs placebo). 42 completed the study. - Increase in the distance walked in the SWT. - Improvement in handgrip strength. - No change in BMI. [165] 300 m g twice weekly for 24 h, transdermal. 6 months 36 elderly women with HF (2:1 vs placebo). - Improvement in the distance walked in the 6MWT. - Increase in peak VO 2 . - Improvement in insulin sensitivity. - No change in body weight or BMI. [166] 100 mg of intramuscular testosterone once every two weeks. 3 months 41 male subjects with CHF and testosterone deficiency (1:1 vs placebo). 29 completed the study. - Similar improvements in SWT, body mass and handgrip strength. - Increase in peak VO 2 . - No differences in BMI. [167] A. Fern andez-Pombo, G. Rodríguez-Carnero, A.I. Castro et al. Clinical Nutrition 40 (2021) 5141e5155 5148 duration and quality of life, as well as a reduction in rates of hospitalisation and mortality [104]. Physical training has shown significant positive results in reducing muscle wasting in these patients [105] since it promotes the proliferation of muscle cells [106] and contributes to reducing inflammation and oxidative damage [107]. It also appears to have a positive role in protein synthesis and interferes with protein degradation pathways [108]. The recommendation of the ESC and ACC/AHA guidelines is to carry out regular aerobic exercise which is capable of causing mild or moderate respiratory distress at the time of its performance [2,99] (level of evidence A recommendation, class I). Resistance exercise training could also be a good strategy to improve skeletal muscle atrophy in subjects with CHF and sarcopenia [109,110]. 7. Drugs with nutritional impact studied in heart failure Although potential therapies for cardiac cachexia in CHF, such as appetite stimulants or anabolic agents (including testosterone) in combination with the application of nutritional supplements and anti-catabolic interventions, are considered in the current ESC guidelines [2], no definitive treatment options have been established for its management. In fact, these guidelines also specify that none of the above-mentioned therapies is of proven benefit and their safety is unknown [2,83]. Although some of them have shown their efficacy in a small number of retrospective analyses and clinical trials, in others their therapeutic appeal is based solely on a theoretical point of view [111]. In addition, studies focused specifically on cardiac cachexia are lacking. Table 2 summarises potential therapeutic options regarding nutritional state and muscle wasting that have been tested in patients with CHF. b 2-agonists are also included in this list of treatments, even though it is known that they can have potentially deleterious effects in these patients [112]. 8. Refeeding syndrome Although there is no single definition of RS, it has been described as a clinical complex accompanied by acute hydroelectrolyte and metabolic alterations (specifically due to an increase in the insulin/glucagon ratio), in patients with malnutrition, as a consequence of the reintroduction of feeding or an increase in the intake of calories (oral, enteral or parenteral) [113]. It can sometimes be fatal, particularly as a result of cardiac involvement, such as congestive HF and arrhythmias, which arise due to electrolyte abnormalities and fluid retention and are the most common causes of sudden death [114]. Figure 3 outlines the causes, pathophysiological mechanisms and clinical effects of RS. Some authors have suggested that hypophosphatemia is the most common abnormal electrolyte in suspected cases. However, potassium and magnesium may be equally important [42]. Thus, when glucose appears in the bloodstream, insulin secretion rises in response [115], and drives not only glucose, but also phosphorus, potassium and magnesium, intracellularly [116]. The hyperinsulinism produced also favours the tubular reabsorption of sodium and water. Thus, this sodium retention and extracellular fluid expansion, together with thiamine (vitamin B 1 )deficiency, can lead to oedema and congestive HF [117]. Phosphate depletion can cause respiratory failure, cardiac arrhythmias and can also cause impaired neuromuscular function with paraesthesiae, seizures, cramps or decreased cardiac contractility [117]. Its depletion likewise decreases the production of 2,3-diphosphoglycerate, causing an increase in haemoglobin oxygen affinity, reduced oxygen release to tissues, and tissue hypoxia [118]. Hypokalaemia and hypomagnesaemia may lead to potentially lethal cardiac arrhythmias, and they can also result in weakness, paralysis or respiratory depression [119,120]. On the other hand, the demand for thiamine also increases during transition from starvation to feeding, as it is a cofactor for glucose-dependent metabolic pathways [42,121]. Its deficiency can lead to neurological alterations (Wernicke's encephalopathy and Korsakoff syndrome) and to congestive HF or wet beriberi due to the decrease in ATP production in cardiac myocytes, among other alterations. Decreased cardiac contractility, arrhythmias or low diastolic blood pressure can also be observed due to the secretion of adenosine [122,123]. The depletion of electrolytes is further exacerbated by conditions such as diarrhoea, loss of intestinal contents, alcoholism, sepsis, diabetes mellitus or exogen insulin administration, diuretic or antiacid use, which cause additional losses [42]. Several RS prevention and treatment protocols have been suggested [117,124e128]. In general, the recommendation is to lowlevel feeding with monitoring, and progress slowly, starting at a maximum of 50% of planned energy intake [117]. Other proposals have established an energy intake of 5e20 kcal/kg/day, depending on the severity of the risk of refeeding, which should gradually be increased over 4e7 days until daily nutritional requirements are met, and the patient is metabolically stable [124e126]. It is widely established that electrolyte deficiencies should be corrected before Table 2 (continued) Therapy Dose Duration Patient population Clinical effects Ref. 250 mg of intramuscular longacting testosterone-enanthate every 4 weeks. 3 months 50 male subjects with CHF (1:1 vs placebo). - Improvement in the distance walked in the 6MWT. - No differences in body weight. [168] 1000 mg of intramuscular longacting testosteroneundecanoate. 4 months 39 male subjects with CHF and testosterone deficiency. 27 completed the study. - Increase in body weight, BMI and lean mass with the combination of exercise training and testosterone therapy. Reduction in the three parameters with testosterone only. - Increase in peak VO 2 . [169] 1000 mg of intramuscular longacting testosteroneundecanoate every 3 months. 12 months 29 male subjects with CHF and testosterone deficiency (1:1 vs placebo). - No improvement in terms of 6MWT. [170] CHF: chronic heart failure; ACE: angiotensin converting enzyme; ARNI: angiotensin receptoreneprilysin inhibitor; ARB: angiotensin receptor blocker; iv: intravenous; VO 2 : oxygen consumption rate; CONUT: controlling nutritional status; GNRI: geriatric nutritional risk index; PNI: prognostic nutritional index; BMI: body mass index; RCT: randomised clinical trial; 6MWT: 6-min walk test; SWT: shuttle walk test. A. Fern andez-Pombo, G. Rodríguez-Carnero, A.I. Castro et al. Clinical Nutrition 40 (2021) 5141e5155 5149