Advertisement

The complex pathophysiology of cardiac cachexia: A review of current pathophysiology and implications for clinical practice

  • Jenjiratchaya Thanapholsart
    Correspondence
    Corresponding author at: Jenjiratchaya Thanapholsart, Division of Applied Technologies for Clinical Care, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, James Clerk Maxwell Building, Waterloo, London, UK.
    Affiliations
    Division of Applied Technologies for Clinical Care, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, James Clerk Maxwell Building, Waterloo, London, UK
    Search for articles by this author
  • Ehsan Khan
    Affiliations
    Department of Adult Nursing, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, James Clerk Maxwell Building, Waterloo, London, UK
    Search for articles by this author
  • Tevfik F. Ismail
    Affiliations
    Cardiology Department, Guy's and St Thomas’ NHS Foundation Trust, London, UK

    School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK
    Search for articles by this author
  • Geraldine A. Lee
    Affiliations
    Division of Applied Technologies for Clinical Care, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, James Clerk Maxwell Building, Waterloo, London, UK
    Search for articles by this author
Open AccessPublished:August 29, 2022DOI:https://doi.org/10.1016/j.amjms.2022.08.016

      Abstract

      Cardiac cachexia is a muscle wasting process that often develops in those with chronic heart failure resulting in weight loss, low levels of physical activity, reduced quality of life, and is associated with a poor prognosis. The pathology of cardiac cachexia is complex with new evidence emerging that implicates several body systems. This review describes the pathophysiology associated with cardiac cachexia and addresses: 1) hormonal changes- neurohormonal abnormalities and metabolic hormone imbalance; 2) mechanisms of muscle wasting in cardiac cachexia, and the integral mechanisms between changed hormones due to cardiac cachexia and muscle wasting processes, and 3) associated abnormalities of gastrointestinal system that contribute to cardiac cachexia. These pleiotropic mechanisms demonstrate the intricate interplay between the affected systems and account for why cardiac cachexia is difficult to manage clinically. This review summarises current pathophysiology of cardiac cachexia and highlights symptoms of cardiac cachexia, implications for clinical practice and research gaps.

      Keywords

      Introduction

      There are multiple terms that identify nutritional status or diseases, such as malnutrition, sarcopenia, cachexia and muscle wasting. Malnutrition is the state of unmet nutritional needs leading to reduced fat free mass and body cell mass as a result in declined physical performance and mental ability, including worsening clinical profile from disease while sarcopenia develops with aging (primary sarcopenia) and factors in addition to ageing (secondary sarcopenia), such as organ failure,
      • Cruz-Jentoft AJ
      • Bahat G
      • Bauer J
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      resulting in losing skeletal muscle mass combined with losing muscle strength and/or decreased physical performance.
      • Meza-Valderrama D
      • Marco E
      • Dávalos-Yerovi V
      • et al.
      Sarcopenia, malnutrition, and cachexia: adapting definitions and terminology of nutritional disorders in older people with cancer.
      However, the definition of sarcopenia remain controversial as it is used for healthy ageing while sarcopenia in chronic disease leads to muscle wasting without the accompanying weight loss.
      • Anker SD
      • Coats AJ
      • Morley JE
      • et al.
      Muscle wasting disease: a proposal for a new disease classification.
      Cachexia is defined as unintentional weight loss due to loss of any tissue caused by chronic disease
      • von Haehling S.
      The wasting continuum in heart failure: from sarcopenia to cachexia.
      ,
      • von Haehling S
      • Ebner N
      • Dos Santos MR
      • Springer J
      • Anker SD
      Muscle wasting and cachexia in heart failure: mechanisms and therapies.
      that results in altered body compositions and imbalances of several body systems.
      • Haehling SV
      • Lainscak M
      • Springer J
      • Anker SD.
      Cardiac cachexia: a systematic overview.
      It is worth noting that the term muscle wasting is recommended in conjunction with sarcopenia and cachexia.
      • Anker SD
      • Coats AJ
      • Morley JE
      • et al.
      Muscle wasting disease: a proposal for a new disease classification.
      Cachexia develops in the advanced stages of chronic diseases, primarily in cancer and chronic heart failure (CHF), chronic kidney disease, and chronic obstructive pulmonary disease.
      • von Haehling S
      • Anker SD.
      Cachexia as a major underestimated and unmet medical need: facts and numbers.
      When CHF related cachexia develops, it is known as cardiac cachexia (CC).
      • von Haehling S
      • Anker SD.
      Cachexia as a major underestimated and unmet medical need: facts and numbers.
      It is estimated that 5-15% of advanced CHF patients have CC, and it is considered a serious complication with a poor prognosis.
      • von Haehling S
      • Anker SD.
      Cachexia as a major underestimated and unmet medical need: facts and numbers.
      In addition, associated co-morbidities or sequelae of CHF, such as atrial fibrillation, lead to an increased risk of developing CC.
      • Arambula-Garza E
      • Castillo-Martinez L
      • Gonzalez-Islas D
      • et al.
      Association of cardiac cachexia and atrial fibrillation in heart failure patients.
      The mortality rate of patients with CC has been reported to increase by 50% within 18 months of diagnosis and therefore is a major mortality risk.
      • Anker SD
      • Ponikowski P
      • Varney S
      • et al.
      Wasting as independent risk factor for mortality in chronic heart failure.
      There are variations in reported prevalence of CC in the literature, reflecting a lack of consensus on the CC diagnostic criteria, with some studies applying 5% as a cut-off point of unintentional weight loss in a previous year as a main criteria,
      • Carson MA
      • Reid J
      • Hill L
      • et al.
      An exploration of the prevalence and experience of cardiac cachexia: protocol for a mixed methods cross-sectional study.
      whereas others have employed ranges of 6%-7.5% as a cut-off points in 6 months.
      • Azhar G
      • Wei JY.
      New approaches to treating cardiac cachexia in the older patient.
      Interestingly, the retrospective study using results from studies that compared enalapril versus (vs) placebo (SOLVD)
      • Investigators S
      • Yusuf S
      • Pitt B
      • Davis CE
      • Hood WB
      • Cohn JN.
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
      or enalapril vs the combination of hydralazine and isosorbide dinitrate (V-HeFTII)
      • Cohn JN
      • Johnson G
      • Ziesche S
      • et al.
      A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.
      suggested that 6% weight loss within 1 year was the strongest predictor of reduced survival when compared to 5%, 7.5%, 10% and 15% weight loss and therefore 6% weight loss should be used as a cut-off point to identify CC. Indeed, the different treatments provided in SOLVD and V-HeFTII might affect the finding on the cut-off points of weight loss on mortality rates, and the study was under powered to examine the differences between both groups.
      • Anker SD
      • Negassa A
      • Coats AJ
      • et al.
      Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study.
      Hence, although various cut-off points have been suggested, according to cachexia consensus, the former cut-off point of 5% weight loss within 12 months is recommended, and a person having two major and three minor criteria can be diagnosed cachexia (Table 1).
      • Evans WJ
      • Morley JE
      • Argiles J
      • et al.
      Cachexia: a new definition.
      Therefore, CC is diagnosed by applying Evans et al (2008) diagnostic criteria. To date, there are no specific criteria for diagnosing CC.
      Table 1Criteria for diagnosing Cardiac Cachexia major and minor criteria.
      Diagnostic Criteria for Cachexia
      Major criteriaMinor criteria
      Chronic diseases, such as chronic heart failure, chronic kidney disease, etc.

      Oedema-free body weight loss > 5% in the past 12 months or BMI < 20kg/m2

      Fatigue, anorexia

      Decreased low fat-free mass index

      Reduced muscle strength

      Haemoglobin ≤ 12 g/dl

      Serum albumin ≤ 3.2 g/dl

      Increase in interleukin-6 > 4.0 pg/ml

      Elevated C-reactive protein > 5.0 mg/l
      Reference: Evans et al. (2008)

      Chronic heart Failure Pathophysiology and Relationship to Cardiac Cachexia

      CHF is caused by numerous pathologies due to abnormal structures and/or functions of the heart leading to increased intracardiac pressures and/or insufficient cardiac output at resting stage and/or during exercise
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
      causing poor perfusion to the vital organs including the kidneys, intestine and skeletal muscle. This in turn triggers neurohormonal abnormalities and immunological activation giving rise to an inflammatory process that leads to muscle wasting.
      • Haehling SV
      • Lainscak M
      • Springer J
      • Anker SD.
      Cardiac cachexia: a systematic overview.
      There are several theories on how CC develops and manifests clinically, including poor gastrointestinal absorption, loss of nutrients in gastrointestinal tracts and imbalances of anabolism and catabolism.
      • Azhar G
      • Wei JY.
      New approaches to treating cardiac cachexia in the older patient.
      The aim is to provide an evidence-based review of the pathology related to CC (in particular in relation to neural and metabolic hormones), how this relates to symptoms experienced by those with CC, and the implication for clinical practice, including the current gaps in research.

      The changes of neural and metabolic hormones in chronic heart failure with cardiac cachexia

      There are two main categories of hormones that involve in the pathophysiology of CC; 1) neurohormones- renin-aldosterone-angiotensin system (RAAS), glucocorticoid hormones, testosterone (Table 2); 2) metabolic hormones- growth hormone, ghrelin, leptin, adiponectin, myostatin and follistatin. The changes of these hormones and their interactions lead to catabolic and anabolic imbalances that subsequently reduce muscle mass as a result in CC (Figure 1). The effects and levels of each hormone due to CC, including the conflicting findings have been reported in the literature.
      Table 2Role of hormones and changes due to cardiac cachexia.
      HormonesGeneral rolesChanges of hormone levels due to cardiac cachexiaPhysiological EffectsConflicting findings
      Neural hormones
      Renin-Aldosterone-Angiotensin system1) Regulating blood volume and systemic vascular resistance.
      • Fountain JH
      • Lappin SL.
      Physiology, Renin Angiotensin System.
      ;

      2) Increasing a release of catecholamines.
      Significantly increased levels of norepinephrine, epinephrine
      • Anker SD
      • Chua TP
      • Ponikowski P
      • et al.
      Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia.
      , AngII levels and renin/angiotensin-mediated aldosterone release were reported in patients with CC than wothout.
      • Nagaya N
      • Uematsu M
      • Kojima M
      • et al.
      Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors.
      - Activation of RAAS leads to poor muscle perfusion, cellular hypoxia
      • Anker SD
      • Chua TP
      • Ponikowski P
      • et al.
      Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia.
      and intestinal perfusion leading to poor nutrient absorption and increased bacterial translocation.
      • Sandek A
      • Rauchhaus M
      • Anker SD
      • von Haehling S.
      The emerging role of the gut in chronic heart failure.


      - Overactivation of β2 adrenoreceptor on skeletal muscle fibres due to increased catecholamines in heart failure could reduce anabolic and anti-catabolic stimuli leading to muscle wasting.
      • Voltarelli VA
      • Bechara LR
      • Bacurau AV
      • et al.
      Lack of β2 -adrenoceptors aggravates heart failure-induced skeletal muscle myopathy in mice.
      N/A
      Glucocorticoids1) Maintaining physical functions under homeostasis; 2) adjusting to changes of environments.
      • Bereshchenko O
      • Bruscoli S
      • Glucocorticoids R.C.
      Sex hormones, and immunity.
      Significantly raised levels of cortisol were seen in patients with CC than without (p < 0.002).
      • Anker SD
      • Chua TP
      • Ponikowski P
      • et al.
      Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia.
      Inhibiting protein and amino acids synthesis
      • Hoberman HD.
      Endocrine regulation of amino acid protein metabolism during fasting.
      and reducing creation of new myofibrillar protein, resulting in muscle atrophy.
      • Braun TP
      • Marks DL.
      The regulation of muscle mass by endogenous glucocorticoids.
      N/A
      Testosterone1) Elevating protein synthesis; 2) Decreasing protein breakdown; 3) Stimulating cell regeneration in skeletal muscles.
      • Josiak K
      • Jankowska EA
      • Piepoli MF
      • Banasiak W
      • Ponikowski P.
      Skeletal myopathy in patients with chronic heart failure: significance of anabolic-androgenic hormones.
      Among CHF patients, low baseline levels of testosterone were reported.
      • Kirby M
      • Hackett G
      • Ramachandran S.
      Testosterone and the Heart.
      A reduction in general metabolism linked to energy expenditure, fatigue, dyspnoea and cachexia in particular.
      • Kirby M
      • Hackett G
      • Ramachandran S.
      Testosterone and the Heart.
      N/A
      Metabolic hormones
      Growth

      hormone
      1) Anabolism and regulating energy stores; 2) GH mostly mediated to act by IGF-1, directly or indirectly.
      • Haehling SV
      • Lainscak M
      • Springer J
      • Anker SD.
      Cardiac cachexia: a systematic overview.
      - Low IGF-1 levels with raised GH level was reported in CHF.
      • Niebauer J
      • Pflaum CD
      • Clark AL
      • et al.
      Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation.


      - The level of GH and IGF-1 in CHF with CC patients can be affected by AngII
      • Brink M
      • Wellen J
      • Delafontaine P.
      Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism.
      , glucocorticoids
      • Brink M
      • Anwar A
      • Delafontaine P.
      Neurohormonal factors in the development of catabolic/anabolic imbalance and cachexia.
      , testosterone and ghrelin.
      • Nagaya N
      • Uematsu M
      • Kojima M
      • et al.
      Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors.
      A low anabolic rate
      • Brink M
      • Anwar A
      • Delafontaine P.
      Neurohormonal factors in the development of catabolic/anabolic imbalance and cachexia.
       and possibly a high catabolic rate
      • Anker SD
      • Chua TP
      • Ponikowski P
      • et al.
      Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia.
       results in muscle depletion.
      N/A
      Ghrelin1) Increasing appetite and GH;

      2) Acting as vasodilation; 3) Cardioprotective; 4) Anti-inflammatory; 5) Increase gastric and intestinal motility.
      • Akalu Y
      • Molla MD
      • Dessie G
      • Ayelign B.
      Physiological effect of ghrelin on body systems.


      - The ghrelin levels found to be significantly higher in CC patients than patients without

      CC.
      • Xin X
      • Ren AJ
      • Zheng X
      • et al.
      Disturbance of circulating ghrelin and obestatin in chronic heart failure patients especially in those with cachexia.
      -

      Ghrelin resistance was reported due to high level of ghrelin caused by inadequate energy.
      • Akamizu T
      • Kangawa K.
      Ghrelin for cachexia.
      Ghrelin potentially leads to muscle wasting in CC.N/A
      Leptin1) Decreasing appetite and lipid synthesis; 2) Increases in energy imbalance and thermogenesis.
      • Conraads VM
      • Hoymans VY
      • Vrints CJ.
      Heart failure and cachexia: insights offered from molecular biology.
      In CC patients, levels of leptin have been reported lower than non- cachectic CHF patients.
      • Doehner W
      • Pflaum CD
      • Rauchhaus M
      • et al.
      Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia.
      Leptin impairs appetite and increases energy expenditure.High leptin levels might be due to elevated energy expenditure
      • Murdoch DR
      • Rooney E
      • Dargie HJ
      • Shapiro D
      • Morton JJ
      • McMurray JJ.
      Inappropriately low plasma leptin concentration in the cachexia associated with chronic heart failure.
      , protective mechanism of leptin to the released TNF-alpha
      • Takahashi N
      • Waelput W
      • Guisez Y.
      Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor.
      , and increased activation of SNS.
      • Trayhurn P
      • Duncan JS
      • Rayner DV.
      Acute cold-induced suppression of ob (obese) gene expression in white adipose tissue of mice: mediation by the sympathetic system.
      Adiponectin1) An anti-inflammatory, insulin-sensitising, and anti-atherogenic adipocytokine
      • Achari AE
      • Jain SK.
      Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction.
      ;

      2) Acting on skeletal muscle by controlling glucose and lipid metabolism.
      • Karbowska J
      • Kochan Z.
      Role of adiponectin in the regulation of carbohydrate and lipid metabolism.
      Adiponectin levels were significantly higher in patients with CC than without
      • Szabó T
      • Scherbakov N
      • Sandek A
      • et al.
      Plasma adiponectin in heart failure with and without cachexia: catabolic signal linking catabolism, symptomatic status, and prognosis.
      , and the level remained significant after adjusting for fat mass
      • Araújo JP
      • Lourenço P
      • Rocha-Gonçalves F
      • Ferreira A
      • Bettencourt P.
      Adiponectin is increased in cardiac cachexia irrespective of body mass index.
      and BMI.
      • McEntegart MB
      • Awede B
      • Petrie MC
      • et al.
      Increase in serum adiponectin concentration in patients with heart failure and cachexia: relationship with leptin, other cytokines, and B-type natriuretic peptide.
      Increased energy expenditure leads to energy deficits resulting in weight loss in CC.
      • Araújo JP
      • Lourenço P
      • Rocha-Gonçalves F
      • Ferreira A
      • Bettencourt P.
      Adiponectin is increased in cardiac cachexia irrespective of body mass index.
      Low level of adiponectin recorded in diabetic patients with CHF regardless of heart failure stage.
      • Baldasseroni S
      • Antenore A
      • Di Serio C
      • et al.
      Adiponectin, diabetes and ischemic heart failure: a challenging relationship.
      MyostatinActing as a potent inhibitor of muscle

      growth.
      • Schiaffino S
      • Dyar KA
      • Ciciliot S
      • Blaauw B
      • Sandri M.
      Mechanisms regulating skeletal muscle growth and atrophy.
      Rising myostatin level from both myocardium of advanced heart failure patients
      • George I
      • Bish LT
      • Kamalakkannan G
      • et al.
      Myostatin activation in patients with advanced heart failure and after mechanical unloading.
      and skeletal muscles due to prolonged cardiac stress contributing to rising circulating serum myostatin.
      • Christensen HM
      • Kistorp C
      • Schou M
      • et al.
      Prevalence of cachexia in chronic heart failure and characteristics of body composition and metabolic status.
      High levels of myostatin lead to skeletal muscle wasting.
      • Elkina Y
      • von Haehling S
      • Anker SD
      • Springer J.
      The role of myostatin in muscle wasting: an overview.
      Myostatin serum was reported lower in patients with CC than without and the reason behind this is that myostatin is mostly found in skeletal muscle rather than serum.
      • Christensen HM
      • Kistorp C
      • Schou M
      • et al.
      Prevalence of cachexia in chronic heart failure and characteristics of body composition and metabolic status.
      FollistatinIncrease muscle mass and strength.
      • Winbanks CE
      • Weeks KL
      • Thomson RE
      • et al.
      Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin.
      No evidence directly linking CC to follistatin, however, follistatin is likely to relate to CC due to its antagonist of myostatin.
      • Kung T
      • Szabo T
      • Springer J
      • Doehner W
      • Anker SD
      • von Haehling S.
      Cachexia in heart disease: highlights from the ESC 2010.
      Inhibiting myostatin signalling in skeletal muscle.
      • Lee SJ
      • McPherron AC.
      Regulation of myostatin activity and muscle growth.
      N/A
      CC=cardiac cachexia, CHF=chronic heart failure, BMI=body mass index, TNF=tumour necrosis factor, SNS=sympathetic nervous system, AngII=angiotensinII, RAAS=renin-aldosterone-angiotensin system, GH= growth hormone, IGF-1=insulin growth factor 1, N/A= not available
      Fig 1
      Fig. 1The diagram illustrates the complex pathophysiology of cardiac cachexia.

      Mechanisms of muscle wasting in cardiac cachexia

      Protein degradation pathways

      There are at least five main pathways of proteolysis: ubiquitin-proteasome pathway (UPP); Ca2+-dependent; lysosomal autophagy; caspase dependent; matrix metalloproteinases
      • Ventadour S
      • Attaix D.
      Mechanisms of skeletal muscle atrophy.
      and mitochondrial dysfunction that can contribute to muscles wasting. This muscle wasting in CHF patients significantly impairs physical exercise tolerance
      • Fonseca G
      • Dos Santos MR
      • de Souza FR
      • et al.
      Discriminating sarcopenia in overweight/obese male patients with heart failure: the influence of body mass index.
      and limits daily activities
      • Fülster S
      • Tacke M
      • Sandek A
      • et al.
      Muscle wasting in patients with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure (SICA-HF).
      affecting quality of life. It is associated with frailty, and this in turn leads to an increased risk of falls and associated risk of fractures and as a consequence hospitalisation.
      • von Haehling S
      • Garfias Macedo T
      • Valentova M
      • et al.
      Muscle wasting as an independent predictor of survival in patients with chronic heart failure.
      UPP is activated by various models that results in muscle wasting.
      • Ventadour S
      • Attaix D.
      Mechanisms of skeletal muscle atrophy.
      The nuclear factor-κB (NF- κB) transcription factor family facilitates the activation of UPP as a major process of muscle catabolism is reported with a recent model highlighting muscle wasting due to cytokines
      • Jackman RW
      • Kandarian SC.
      The molecular basis of skeletal muscle atrophy.
      and the presence of reactive oxygen species (ROS).
      • Aiken CT
      • Kaake RM
      • Wang X
      • Huang L.
      Oxidative stress-mediated regulation of proteasome complexes.
      The muscle-specific E3 ligase; the components of the UPP, which has muscle ring finger 1(MuRF-1) as a component,
      • Penna F
      • Ballarò R
      • Beltrà M
      • De Lucia S
      • García Castillo L
      • Costelli P
      The skeletal muscle as an active player against cancer cachexia.
      can also be stimulated by NF-κB.
      • Cai D
      • Frantz JD
      • Tawa Jr., NE
      • et al.
      IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.
      Although, they act via different pathways, activation of NF-κB increase MuRF-1 which mediates UPP, results in muscle wasting.
      • Cai D
      • Frantz JD
      • Tawa Jr., NE
      • et al.
      IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.
      A study reported that increases in MuRF-1 in skeletal muscle of CHF patients was significantly higher than in a healthy control group.
      • Gielen S
      • Sandri M
      • Kozarez I
      • et al.
      Exercise training attenuates MuRF-1 expression in the skeletal muscle of patients with chronic heart failure independent of age: the randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging catabolism study.
      Additionally, the activation of NF-κB can also be stimulated by activation of neurohormones: AngII
      • Yoshida T
      • Tabony AM
      • Galvez S
      • et al.
      Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia.
      and aldosterone,
      • Azhar G
      • Wei JY.
      New approaches to treating cardiac cachexia in the older patient.
      and metabolic hormones: glucocorticoids
      • Sato AY
      • Richardson D
      • Cregor M
      • et al.
      Glucocorticoids induce bone and muscle atrophy by tissue-specific mechanisms upstream of E3 ubiquitin ligases.
      and myostatin, including pro-inflammatory cytokines, such as IL-1
      • Webster JM
      • Kempen LJAP
      • Hardy RS
      • Langen RCJ.
      Inflammation and skeletal muscle wasting during cachexia.
      and in particular TNF- α,
      • Schiaffino S
      • Dyar KA
      • Ciciliot S
      • Blaauw B
      • Sandri M.
      Mechanisms regulating skeletal muscle growth and atrophy.
      and high levels of these hormones and cytokines were observed among CHF with CC. Thus, together these mechanisms cause muscle depletion and atrophy seen in CC via activation of UPP, and CHF patients are highly likely to develop muscle loss.
      Another important protein degradation pathway is lysosomal autophagy.
      • Penna F
      • Ballarò R
      • Beltrà M
      • De Lucia S
      • García Castillo L
      • Costelli P
      The skeletal muscle as an active player against cancer cachexia.
      Autophagy is a process that preserves protein homeostasis via lysosomal-dependent degradation, that breaks down long-lived protein, preventing accumulation of redundant or defective proteins.
      • Loncar G
      • Springer J
      • Anker M
      • Doehner W
      • Lainscak M.
      Cardiac cachexia: hic et nunc.
      It has been suggested that the autophagy process might occur simultaneously with cachexia, resulting in muscle wasting.
      • Zhang Y
      • Wang J
      • Wang X
      • et al.
      The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia.
      It was evident that mitochondrial dysfunction has a negative impact on both myocardium and skeletal muscles in CC. This might be due to decreased mitochondrial oxidative capacity as a result of reduced adenosine triphosphate (ATP)-energy carrier in cell- and increased production of ROS as a consequence of the activation of the inflammatory process.
      • VanderVeen BN
      • Fix DK
      • Carson JA.
      Disrupted skeletal muscle mitochondrial dynamics, mitophagy, and biogenesis during cancer cachexia: a role for inflammation.
      In CHF, mitochondrial dysfunction plays an important role as its reduced function decreases the energy to support cardiac contraction and relaxation.
      • Sabbah HN.
      Targeting the mitochondria in heart failure: a translational perspective.
      Similarly, reduced mitochondrial oxidative capacity has been reported resulting in a decline of energy production in skeletal muscles in CHF.
      • Rosca MG
      • Hoppel CL.
      Mitochondrial dysfunction in heart failure.
      This process might be the reason behind HF-related to exercise intolerance due to mitochondria dysfunction,
      • Sabbah HN
      • Gupta RC
      • Singh-Gupta V
      • Zhang K.
      Effects of elamipretide on skeletal muscle in dogs with experimentally induced heart failure.
      resulting in muscle wasting.
      Apoptosis is identified as unwanted cells or damaged cells, such as cellular shrinkage, formation of apoptosis body.
      • Yoon S
      • Park SJ
      • Han JH
      • et al.
      Caspase-dependent cell death-associated release of nucleosome and damage-associated molecular patterns.
      These are caused by caspase, a family of cysteine proteases, in other words, caspase-mediated apoptosis.
      • Yoon S
      • Park SJ
      • Han JH
      • et al.
      Caspase-dependent cell death-associated release of nucleosome and damage-associated molecular patterns.
      Apoptosis and caspase-mediated apoptosis might be seen in CC due to its association with mitochondrial dysfunction.
      • VanderVeen BN
      • Fix DK
      • Carson JA.
      Disrupted skeletal muscle mitochondrial dynamics, mitophagy, and biogenesis during cancer cachexia: a role for inflammation.
      However, there were no differences in apoptosis between those with CC or without.
      • Filippatos GS
      • Kanatselos C
      • Manolatos DD
      • et al.
      Studies on apoptosis and fibrosis in skeletal musculature: a comparison of heart failure patients with and without cardiac cachexia.
      Indeed, the collagen-causing fibrosis was significantly found in patients with CC compared to those without. Collagen accumulation leads to fibrosis in skeletal muscles resulting in muscle wasting related to exercise intolerance.
      • Filippatos GS
      • Kanatselos C
      • Manolatos DD
      • et al.
      Studies on apoptosis and fibrosis in skeletal musculature: a comparison of heart failure patients with and without cardiac cachexia.
      Thus, protein degradation pathways appear to play a significant role in the muscle wasting process via several mechanisms.

      Immunological activation

      Cytokines, such as tumour necrosis factor (TNF) α, interleukin (IL)-1; IL-1α and IL-1β,
      • Dinarello CA.
      Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.
      IL-6, and interferon-γ which augments catabolism in the body are mainly produced by monocytes and macrophages.
      • Springer J
      • Filippatos G
      • Akashi YJ
      • Anker SD.
      Prognosis and therapy approaches of cardiac cachexia.
      Endothelial cells and myocardium are also reported to release inflammatory cytokines, and the myocardial response leads to the hypothesis that hypoxia might lead to increased pro-inflammatory cytokine secretion in CHF, with the failing heart might be the major source of TNF-α.
      • Springer J
      • Filippatos G
      • Akashi YJ
      • Anker SD.
      Prognosis and therapy approaches of cardiac cachexia.
      The release of these cytokines due to CHF can be as a result of homeostatic imbalance, activation of neurohormones; catecholamines, aldosterone, AngII
      • Anker SD
      • Ponikowski PP
      • Clark AL
      • et al.
      Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure.
      ; and increasing levels of endotoxin such as lipopolysaccharides (LPS), resulting from bowel wall oedema and bacterial translocation.
      • Niebauer J
      • Volk HD
      • Kemp M
      • et al.
      Endotoxin and immune activation in chronic heart failure: a prospective cohort study.
      Interestingly, IL-1β increases levels of the adrenocorticotropic hormone and cortisol
      • Laird BJ
      • McMillan D
      • Skipworth RJE
      • et al.
      The emerging role of interleukin 1β (IL-1β) in cancer cachexia.
      which may facilitate catabolism in cachexia (Table 2).
      • Ericsson A
      • Kovács KJ
      • Sawchenko PE.
      A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons.
      TNF-α, IL-1 and IL-6 signal NF-κB
      • Webster JM
      • Kempen LJAP
      • Hardy RS
      • Langen RCJ.
      Inflammation and skeletal muscle wasting during cachexia.
      • Freire PP
      • Cury SS
      • Lopes LO
      • et al.
      Decreased miR-497-5p suppresses IL-6 induced atrophy in muscle cells.
      , and activation of NF-κB itself can also produce IL-1, TNF- α,
      • Haehling SV
      • Genth-Zotz S
      • Anker SD
      • Volk HD.
      Cachexia: a therapeutic approach beyond cytokine antagonism.
      IL-6 that can establish an autoregulatory feedback loop.
      • Ghosh S
      • May MJ
      • Kopp EB.
      NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses.
      IL-6 could also be secreted by IL-1.
      • Loppnow H
      • Libby P.
      Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1.
      All these cytokines trigger upregulation of the UPP increasing protein degradation and increased resting energy expenditure in CHF patients contributing to muscle wasting (which is seen in CC) as indicated in the protein degradation pathway section. TNF- α and other types of cytokines; IL-1, IL-6, also reduce appetite through the activation of anorexigenic agents; such as corticotropin-releasing factor, and inhibition of orexigenic neuropeptide-Y in hypothalamus.
      • Patsalos O
      • Dalton B
      • Leppanen J
      • Ibrahim MAA
      • Himmerich H.
      Impact of TNF-α inhibitors on body weight and BMI: a systematic review and meta-analysis.
      This means that a raise in TNF-α may cause an imbalance between energy consumption and expenditure.
      TNF-α is a fundamental cytokine that was found to significantly correlate with weight loss in CC patients (r = 0.78, p = .0003).
      • Anker SD
      • Chua TP
      • Ponikowski P
      • et al.
      Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia.
      The levels of TNF-α were significantly higher in CHF patients with CC compared to non-cachectic CHF patients,
      • Gaggin HK
      • Belcher AM
      • Gandhi PU
      • Ibrahim NE
      • Januzzi Jr., JL
      Serial echocardiographic characteristics, novel biomarkers and cachexia development in patients with stable chronic heart failure.
      suggesting that TNF-α plays a role in inducing cachexia. As well as the effect of TNF-α on the muscles, it also increases gut permeability. In addition to TNF-α, the level of cytokines; IL-6, in the circulation increases significantly in CHF patients, with even greater levels noted in CC patients compared to non-cachectic CHF patients.
      • Nagaya N
      • Uematsu M
      • Kojima M
      • et al.
      Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors.
      Also, the elevation of IL-6 causes hypoferremia
      • Nemeth E
      • Rivera S
      • Gabayan V
      • et al.
      IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.
      triggered by hepcidin-liver peptides that primarily control systemic iron balance produced by hepatocytes-
      • Pagani A
      • Nai A
      • Silvestri L
      • Camaschella C.
      Hepcidin and anemia: a tight relationship.
      possibly leading to iron deficiency (ID).
      In conclusion, immunological activation in CC due to CHF can worsen muscle wasting through the protein degradation pathway and lead to an imbalance of catabolism and anabolism.

      Abnormalities of gastrointestinal tract

      CHF reduces cardiac output stimulating the SNS which results in a diversion of blood from the gastrointestinal tract to the core circulation. The reduction in systolic blood supply of 58%, 55% and 57% respectively to the celiac trunk, superior mesenteric artery , and inferior mesenteric artery in CC were reported compared to the control group.
      • Sandek A
      • Swidsinski A
      • Schroedl W
      • et al.
      Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia.
      Reduced blood flow perfusion in the bowel causes mucosal ischaemia, acidosis, and elevated epithelial permeability or a ‘leaky gut’.
      • Sandek A
      • Swidsinski A
      • Schroedl W
      • et al.
      Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia.
      These physiological responses in the gastrointestinal tract may be responsible for bacterial translocation leading to endotoxin release and immune activation.
      • Sundaram V
      • Fang JC.
      Gastrointestinal and liver issues in heart failure.
      Gram negative LPS-endotoxin is a strong inducer of pro-inflammatory cytokines, particularly TNF-α,
      • Anker SD
      • Egerer KR
      • Volk H-D
      • Kox WJ
      • Poole-Wilson PA
      • Coats AJS.
      Elevated soluble CD14 receptors and altered cytokines in chronic heart failure.
      and antibody Immunoglobulin A (IgA).
      • Sandek A
      • Swidsinski A
      • Schroedl W
      • et al.
      Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia.
      In addition, the release of IgA; activation of immunological defence, was found to be responsible for an increase in juxtamucosal bacterial concentration with bacterial attachment to biofilm.
      • Sandek A
      • Swidsinski A
      • Schroedl W
      • et al.
      Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia.
      This might further augment systemic inflammation in CHF.
      Besides the rise in LPS, increased venous congestion due to CHF also causes bowel wall oedema.
      • Valentova M
      • von Haehling S
      • Krause C
      • et al.
      Cardiac cachexia is associated with right ventricular failure and liver dysfunction.
      This bowel wall oedema is found between the intestinal epithelium and mesenteric capillary that increases the gap between capillary wall and enterocyte membrane in all parts of the intestine in heart failure.
      • Polsinelli VB
      • Sinha A
      • Shah SJ.
      Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment.
      The greatest distance between the basal wall of the enterocyte and the capillary wall and highest collagen content of the mucosal wall in small intestines were seen in CC patients compared to CHF patients without CC and healthy control.
      • Arutyunov GP
      • Kostyukevich OI
      • Serov RA
      • Rylova NV
      • Bylova NA.
      Collagen accumulation and dysfunctional mucosal barrier of the small intestine in patients with chronic heart failure.
      These physical bowel changes are thought to be the causes of reduced iron absorption
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
      leading to ID,
      • Anand IS
      • Gupta P.
      Anemia and iron deficiency in heart failure.
      protein, fat and possibly medicine absorption in patients CC than without.
      • Arutyunov GP
      • Kostyukevich OI
      • Serov RA
      • Rylova NV
      • Bylova NA.
      Collagen accumulation and dysfunctional mucosal barrier of the small intestine in patients with chronic heart failure.
      The occurrence of paracellular passive permeability together with altered intestinal bacteria further deteriorates gut permeability.
      • Sandek A
      • Bauditz J
      • Swidsinski A
      • et al.
      Altered intestinal function in patients with chronic heart failure.
      Increased gut permeability results in poor absorption of carbohydrates in the form of lactulose/mannitol and sucralose.
      • Sandek A
      • Bauditz J
      • Swidsinski A
      • et al.
      Altered intestinal function in patients with chronic heart failure.
      These findings support the presence of bowel wall oedema and increased gut permeability resulting in CC due to impaired nutrient absorption, contributing to accelerated catabolic process.

      Cardiac-cachectic symptoms and management

      Clinically, changes in the gastrointestinal system cause abdominal discomfort
      • Valentova M
      • von Haehling S
      • Bauditz J
      • et al.
      Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure.
      together with the changes in numerous hormones as mentioned above (growth hormone, leptin, ghrelin, and alternations of smell and taste perception),
      • von Haehling S
      • Doehner W
      • Anker SD.
      Nutrition, metabolism, and the complex pathophysiology of cachexia in chronic heart failure.
      increases the likelihood of heart failure patients experiencing lack of appetite or worsening appetite in CC.
      • Sandek A
      • Swidsinski A
      • Schroedl W
      • et al.
      Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia.
      Gastrointestinal symptoms such as severe nausea or vomiting and burping, have been observed in CHF with CC.
      • Valentova M
      • von Haehling S
      • Bauditz J
      • et al.
      Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure.
      The worsening of these symptoms have a negative impact on nutrient intake, adding to the catabolic and anabolic imbalance.
      • Valentova M
      • von Haehling S
      • Bauditz J
      • et al.
      Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure.
      ID due to CHF results in reduced physical activity as seen with 6-minute walking test compared to non-ID group (p<0.001).
      • van der Wal HH
      • Grote Beverborg N
      • Dickstein K
      • et al.
      Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use.
      This impaired physical activity together with the activation of chronic inflammatory process in HF
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
      and protein degradation pathway might worsen exercise tolerance among CC patients causing fatigue and muscle depletion.

      Implication for clinical practice and future research development

      The literature review has highlighted the variance in reported diagnostic cut off points leading to conflicting prevalence and survival rates. This variance has led to a lack of consensus on the severity of CC and treatments. The recent consensus on the cachexia diagnostic criteria
      • Evans WJ
      • Morley JE
      • Argiles J
      • et al.
      Cachexia: a new definition.
      needs to be adapted so that early detection can be optimised which has the potential to reduce mortality.
      • von Haehling S
      • Garfias Macedo T
      • Valentova M
      • et al.
      Muscle wasting as an independent predictor of survival in patients with chronic heart failure.
      There is an under-diagnosis and under-assessment for cachexia or muscle wasting in patients with cardiovascular disease.
      • von Haehling S
      • Ebner N
      • Dos Santos MR
      • Springer J
      • Anker SD
      Muscle wasting and cachexia in heart failure: mechanisms and therapies.
      This is likely due to oedema masking true body compositions. Expensive anthropometric measurements such as DEXA and MRI are also not always available.
      • Cruz-Jentoft AJ
      • Bahat G
      • Bauer J
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      Cancer services have addressed this with a simplification for diagnosis, but this has not been validated in HF patients.
      • Argiles J
      • Madeddu C
      • Moreno C
      • et al.
      CASC-IN: A New Tool to Diagnose Pre-Cachexia in Cancer Patients.
      Muscle wasting can be accelerated via SNS activation along with increasing levels of catecholamines and RAAS that are evident in HF and therefore early medication initiation with ACEIs
      • Saha S
      • Singh PK
      • Roy P
      • Kakar SS.
      Cardiac cachexia: unaddressed aspect in cancer patients.
      and beta-blockers
      • Clark AL
      • Coats AJS
      • Krum H
      • et al.
      Effect of beta-adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial.
      have the potential to slow down the muscle wasting process.
      Parenteral ghrelin administration shows promising results in CC patients with positive effects on lean body mass, muscle strength, improvement of cardiac structure and function, reducing norepinephrine, epinephrine and BNP.
      • Nagaya N
      • Moriya J
      • Yasumura Y
      • et al.
      Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure.
      Similarly, in a meta-analysis study of cancer-related cachexia, the oral form of ghrelin agonist; anamorelin, demonstrated statistically significant increases in body lean mass (and total body weight.
      • Nishie K
      • Yamamoto S
      • Nagata C
      • Koizumi T
      • Hanaoka M.
      Anamorelin for advanced non-small-cell lung cancer with cachexia: systematic review and meta-analysis.
      Currently, anamorelin is in clinical trial phase III with results expected.
      • Ebner N
      • Anker SD
      • von Haehling S.
      Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference.
      Iron deficiency in CHF and CC should be treated with intravenous iron showing significant improvements in exercise tolerance using the 6 minute walk test (p<0.0001).
      • Jankowska EA
      • Tkaczyszyn M
      • Suchocki T
      • et al.
      Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials.
      Although the European Society of Cardiology (ESC) Guidelines recommend ferric carboxymaltose in acute and chronic HF to improve symptoms, physical performance and quality of life in patients with HF and LVEF ≤ 45%,
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
      evidence is lacking for its use in CC.
      The pharmacological target to treat cachexia is now the Act-R ligands due to its effect on activated muscle wasting.
      • Ebner N
      • Anker SD
      • von Haehling S.
      Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference.
      In the RCT study, bimagrumab; the inhibitor of ActRIIA and ActRIIB, was tested in elderly with sarcopenia which reported bimagrumab significantly increasing lean muscle mass (P<0.001) but no significant changes in physical performance (P > 0.05) when compared to control group.
      • Rooks D
      • Swan T
      • Goswami B
      • et al.
      Bimagrumab vs optimized standard of care for treatment of sarcopenia in community-dwelling older adults: a randomized clinical trial.
      Further studies on bimagrumab in CC patients are required.
      IL-1 signal blockade may be a reasonable target for muscles wasting caused by chronic disease
      • Cheung WW
      • Zheng R
      • Hao S
      • et al.
      The role of IL-1 in adipose browning and muscle wasting in CKD-associated cachexia.
      with evidence of decreased levels of CRP and IL-6 with IL-1 blockade-anakinra.
      • Van Tassell BW
      • Arena RA
      • Toldo S
      • et al.
      Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure.
      This in line with the recent conference presentations suggesting that IL-1 signalling pathway blockade may reduce inflammatory markers.
      • Ebner N
      • Anker SD
      • von Haehling S.
      Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference.
      Bowel wall oedema can cause poor nutrient absorption due to bacterial translocation, and elevating bowel movement (using metoclopramide) or curbing bacteria overgrowth (using lactobacilli) could indirectly decrease bowel wall oedema as a result in improved food absorption.
      • Azhar G
      • Wei JY.
      New approaches to treating cardiac cachexia in the older patient.
      Prescribing antibiotics to reduce intestinal bacterial translocation is not advised with the adverse effects on the gut microflora.
      • Okoshi MP
      • Capalbo RV
      • Romeiro FG
      • Okoshi K.
      Cardiac cachexia: perspectives for prevention and treatment.
      Undoubtedly, this area of research will continue as we understand more about the gut microbiome.
      Testosterone can be used to improve muscle strength and exercise capacity but its associated increase in cardiovascular adverse effects cannot be ignored, especially when orally administered.
      • Borst SE
      • Shuster JJ
      • Zou B
      • et al.
      Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis.
      The combination of nutritional support and aerobic exercise should be provided as it might be appropriate to manage CC symptoms. This is because dietary support; high calories and protein supplements, help to compensate excessive catabolism and build the muscle
      • Fernández-Pombo A
      • Rodríguez-Carnero G
      • Castro AI
      • et al.
      Relevance of nutritional assessment and treatment to counteract cardiac cachexia and sarcopenia in chronic heart failure.
      while the latter restores the proteasome overactivation and protect the oxidation stress and UPS overactivation
      • Cunha TF
      • Bacurau AVN
      • Moreira JBN
      • et al.
      Exercise training prevents oxidative stress and ubiquitin-proteasome system overactivity and reverse skeletal muscle atrophy in heart failure.
      as bowel oedema can be decreased with improved food absorption, and as a consequence a reduction in muscle wastage. Likewise, exercise-based cardiac rehabilitation is recommended in the ESC heart failure Guidelines.
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
      Branched-chain amino acids (BCAA) with provided resistance exercise training have shown significant improvement of HF symptoms- dypnone and fatigue
      • Pineda-Juárez JA
      • Sánchez-Ortiz NA
      • Castillo-Martínez L
      • et al.
      Changes in body composition in heart failure patients after a resistance exercise program and branched chain amino acid supplementation.
      - when compared to the group with exercise alone while another study by Azhar et al. (2020) reports a significant reduction of pulse pressure and heart rates and improved exercise tolerance using whey protein with exercise training compared to whey protein alone and (p < 0.05).
      • Azhar G
      • Raza S
      • Pangle A
      • et al.
      Potential beneficial effects of dietary protein supplementation and exercise on functional capacity in a pilot study of individuals with heart failure with preserved ejection fraction.
      This approach of nutritional and physical training support has potential but larger randomised control trial studies are needed.
      Fish oil-omega-3 polyunsaturated fatty acids; PUFA-, containing rich protein, rich calories, nutritional supplements and important amino acid have been used in CC patients
      • von Haehling S
      • Ebner N
      • dos Santos MR
      • Springer J
      • Anker SD.
      Muscle wasting and cachexia in heart failure: mechanisms and therapies.
      and shown to reduce TNF-α.
      • Mehra MR
      • Lavie CJ
      • Ventura HO
      • Milani RV.
      Fish oils produce anti-inflammatory effects and improve body weight in severe heart failure.
      PUFA together with BCAA have potential benefits but extensive evidence is currently lacking.
      • von Haehling S
      • Ebner N
      • dos Santos MR
      • Springer J
      • Anker SD.
      Muscle wasting and cachexia in heart failure: mechanisms and therapies.
      There is a need to involve the multidisciplinary team with the cardiologist, physiotherapist, dietician, pharmacologist and cardiac nurse, to provide comprehensive care and treatment to HF patients with CC and has the potential to improve self-management as seen in HF.

      Conclusions

      This review has demonstrated the complexity of the pathophysiology of CC in relation to heart failure that is primarily driven by neural and metabolic hormonal changes, the activation of inflammatory process due to cytokines, protein degradation and abnormal gastrointestinal systems leading to a multitude of symptoms. The understanding of pathophysiology of CC can play a role in developing beneficial treatments and this review highlights the lack of robust evidence to support any one treatment.
      The immediate priority is to improve the assessment and diagnosis of CC as early detection allows for early treatment and optimisation of medications etc as well as promoting a multidisciplinary approach to managing this complex condition. The development of effective evidenced-based CC treatments is urgently needed.

      Authors contributions statement

      Jenjiratchaya Thanapholsart, Dr Ehsan Khan, Dr Tevfik F. Ismail and Dr Geraldine A. Lee desinged the concept of the work, methodology and the diagram of pathophysiology of CC; Jenjiratchaya Thanapholsart wrote the original draft, drew the orginal diagram, performed data curation and formal analysis. Dr Ehsan Khan, Dr Tevfik F. Ismail and Dr Geraldine A. Lee supervised and substantially reviewed and edited the work and the diagram.

      Acknowledgement

      Many thanks to the Royal Thai Government for the PhD scholarship.

      Sources of Funding

      No funding.

      Declaration of Competing Interest

      There are no conflicts of interest.

      References

        • Cruz-Jentoft AJ
        • Bahat G
        • Bauer J
        • et al.
        Sarcopenia: revised European consensus on definition and diagnosis.
        Age Ageing. 2019; 48: 16-31
        • Meza-Valderrama D
        • Marco E
        • Dávalos-Yerovi V
        • et al.
        Sarcopenia, malnutrition, and cachexia: adapting definitions and terminology of nutritional disorders in older people with cancer.
        Nutrients. 2021; 13: 761
        • Anker SD
        • Coats AJ
        • Morley JE
        • et al.
        Muscle wasting disease: a proposal for a new disease classification.
        J Cachexia Sarcopenia Muscle. 2014; 5: 1-3
        • von Haehling S.
        The wasting continuum in heart failure: from sarcopenia to cachexia.
        Proc Nutr Soc. 2015; 74: 367-377
        • von Haehling S
        • Ebner N
        • Dos Santos MR
        • Springer J
        • Anker SD
        Muscle wasting and cachexia in heart failure: mechanisms and therapies.
        Nat Rev Cardiol. 2017; 14: 323-341
        • Haehling SV
        • Lainscak M
        • Springer J
        • Anker SD.
        Cardiac cachexia: a systematic overview.
        Pharmacol Ther. 2009; 121: 227-252
        • von Haehling S
        • Anker SD.
        Cachexia as a major underestimated and unmet medical need: facts and numbers.
        J Cachexia Sarcopenia Muscle. 2010; 1: 1-5
        • Arambula-Garza E
        • Castillo-Martinez L
        • Gonzalez-Islas D
        • et al.
        Association of cardiac cachexia and atrial fibrillation in heart failure patients.
        Int J Cardiol. 2016; 223: 863-866
        • Anker SD
        • Ponikowski P
        • Varney S
        • et al.
        Wasting as independent risk factor for mortality in chronic heart failure.
        Lancet. 1997; 349: 1050-1053
        • Carson MA
        • Reid J
        • Hill L
        • et al.
        An exploration of the prevalence and experience of cardiac cachexia: protocol for a mixed methods cross-sectional study.
        BMC Palliat Care. 2019; 18: 82
        • Azhar G
        • Wei JY.
        New approaches to treating cardiac cachexia in the older patient.
        Curr Cardiovasc Risk Rep. 2013; 7: 480-484
        • Investigators S
        • Yusuf S
        • Pitt B
        • Davis CE
        • Hood WB
        • Cohn JN.
        Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
        N Engl J Med. 1991; 325: 293-302
        • Cohn JN
        • Johnson G
        • Ziesche S
        • et al.
        A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.
        N Engl J Med. 1991; 325: 303-310
        • Anker SD
        • Negassa A
        • Coats AJ
        • et al.
        Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study.
        Lancet. 2003; 361: 1077-1083
        • Evans WJ
        • Morley JE
        • Argiles J
        • et al.
        Cachexia: a new definition.
        Clin Nutr. 2008; 27: 793-799
        • McDonagh TA
        • Metra M
        • Adamo M
        • et al.
        2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
        Eur Heart J. 2021; 42: 3599-3726
        • Fountain JH
        • Lappin SL.
        Physiology, Renin Angiotensin System.
        https://www.ncbi.nlm.nih.gov/books/NBK470410/
        Date: 2020
        Date accessed: April 1, 2020
        • Anker SD
        • Chua TP
        • Ponikowski P
        • et al.
        Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia.
        Circulation. 1997; 96: 526-534
        • Nagaya N
        • Uematsu M
        • Kojima M
        • et al.
        Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors.
        Circulation. 2001; 104: 2034-2038
        • Sandek A
        • Rauchhaus M
        • Anker SD
        • von Haehling S.
        The emerging role of the gut in chronic heart failure.
        Curr Opin Clin Nutr Metab Care. 2008; 11: 632-639
        • Voltarelli VA
        • Bechara LR
        • Bacurau AV
        • et al.
        Lack of β2 -adrenoceptors aggravates heart failure-induced skeletal muscle myopathy in mice.
        J Cell Mol Med. 2014; 18: 1087-1097
        • Bereshchenko O
        • Bruscoli S
        • Glucocorticoids R.C.
        Sex hormones, and immunity.
        Front Immunol. 2018; 9 (-32): 1332
        • Hoberman HD.
        Endocrine regulation of amino acid protein metabolism during fasting.
        Yale J Biol Med. 1950; 22: 341-367
        • Braun TP
        • Marks DL.
        The regulation of muscle mass by endogenous glucocorticoids.
        Front Physiol. 2015; 6: 12
        • Josiak K
        • Jankowska EA
        • Piepoli MF
        • Banasiak W
        • Ponikowski P.
        Skeletal myopathy in patients with chronic heart failure: significance of anabolic-androgenic hormones.
        J Cachexia Sarcopenia Muscle. 2014; 5: 287-296
        • Kirby M
        • Hackett G
        • Ramachandran S.
        Testosterone and the Heart.
        Eur Cardiol. 2019; 14: 103-110
        • Niebauer J
        • Pflaum CD
        • Clark AL
        • et al.
        Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation.
        J Am Coll Cardiol. 1998; 32: 393-397
        • Brink M
        • Wellen J
        • Delafontaine P.
        Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism.
        J Clin Invest. 1996; 97: 2509-2516
        • Brink M
        • Anwar A
        • Delafontaine P.
        Neurohormonal factors in the development of catabolic/anabolic imbalance and cachexia.
        Int J Cardiol. 2002; 85 (discussion 21-4): 111-121
        • Akalu Y
        • Molla MD
        • Dessie G
        • Ayelign B.
        Physiological effect of ghrelin on body systems.
        Int J Endocrinol. 2020; 20201385138
        • Xin X
        • Ren AJ
        • Zheng X
        • et al.
        Disturbance of circulating ghrelin and obestatin in chronic heart failure patients especially in those with cachexia.
        Peptides. 2009; 30: 2281-2285
        • Akamizu T
        • Kangawa K.
        Ghrelin for cachexia.
        J Cachexia Sarcopenia Muscle. 2010; 1: 169-176
        • Conraads VM
        • Hoymans VY
        • Vrints CJ.
        Heart failure and cachexia: insights offered from molecular biology.
        Front Biosci. 2008; 13: 325-335
        • Doehner W
        • Pflaum CD
        • Rauchhaus M
        • et al.
        Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia.
        Eur J Endocrinol. 2001; 145: 727-735
        • Murdoch DR
        • Rooney E
        • Dargie HJ
        • Shapiro D
        • Morton JJ
        • McMurray JJ.
        Inappropriately low plasma leptin concentration in the cachexia associated with chronic heart failure.
        Heart. 1999; 82: 352-356
        • Takahashi N
        • Waelput W
        • Guisez Y.
        Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor.
        J Exp Med. 1999; 189: 207-212
        • Trayhurn P
        • Duncan JS
        • Rayner DV.
        Acute cold-induced suppression of ob (obese) gene expression in white adipose tissue of mice: mediation by the sympathetic system.
        Biochem J. 1995; 311: 729-733
        • Achari AE
        • Jain SK.
        Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction.
        Int J Mol Sci. 2017; 18
        • Karbowska J
        • Kochan Z.
        Role of adiponectin in the regulation of carbohydrate and lipid metabolism.
        J Physiol Pharmacol. 2006; 57: 103-113
        • Szabó T
        • Scherbakov N
        • Sandek A
        • et al.
        Plasma adiponectin in heart failure with and without cachexia: catabolic signal linking catabolism, symptomatic status, and prognosis.
        Nutr Metab Cardiovasc Dis. 2014; 24: 50-56
        • Araújo JP
        • Lourenço P
        • Rocha-Gonçalves F
        • Ferreira A
        • Bettencourt P.
        Adiponectin is increased in cardiac cachexia irrespective of body mass index.
        Eur J Heart Fail. 2009; 11: 567-572
        • McEntegart MB
        • Awede B
        • Petrie MC
        • et al.
        Increase in serum adiponectin concentration in patients with heart failure and cachexia: relationship with leptin, other cytokines, and B-type natriuretic peptide.
        Eur Heart J. 2007; 28: 829-835
        • Baldasseroni S
        • Antenore A
        • Di Serio C
        • et al.
        Adiponectin, diabetes and ischemic heart failure: a challenging relationship.
        Cardiovasc Diabetol. 2012; 11: 151
        • Schiaffino S
        • Dyar KA
        • Ciciliot S
        • Blaauw B
        • Sandri M.
        Mechanisms regulating skeletal muscle growth and atrophy.
        FEBS J. 2013; 280: 4294-4314
        • George I
        • Bish LT
        • Kamalakkannan G
        • et al.
        Myostatin activation in patients with advanced heart failure and after mechanical unloading.
        Eur J Heart Fail. 2010; 12: 444-453
        • Christensen HM
        • Kistorp C
        • Schou M
        • et al.
        Prevalence of cachexia in chronic heart failure and characteristics of body composition and metabolic status.
        Endocrine. 2013; 43: 626-634
        • Elkina Y
        • von Haehling S
        • Anker SD
        • Springer J.
        The role of myostatin in muscle wasting: an overview.
        J Cachexia Sarcopenia Muscle. 2011; 2: 143-151
        • Winbanks CE
        • Weeks KL
        • Thomson RE
        • et al.
        Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin.
        J Cell Biol. 2012; 197: 997-1008
        • Kung T
        • Szabo T
        • Springer J
        • Doehner W
        • Anker SD
        • von Haehling S.
        Cachexia in heart disease: highlights from the ESC 2010.
        J Cachexia Sarcopenia Muscle. 2011; 2: 63-69
        • Lee SJ
        • McPherron AC.
        Regulation of myostatin activity and muscle growth.
        Proc Natl Acad Sci U S A. 2001; 98: 9306-9311
        • Ventadour S
        • Attaix D.
        Mechanisms of skeletal muscle atrophy.
        Curr Opin Rheumatol. 2006; 18: 631-635
        • Fonseca G
        • Dos Santos MR
        • de Souza FR
        • et al.
        Discriminating sarcopenia in overweight/obese male patients with heart failure: the influence of body mass index.
        ESC Heart Fail. 2020; 7: 84-91
        • Fülster S
        • Tacke M
        • Sandek A
        • et al.
        Muscle wasting in patients with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure (SICA-HF).
        Eur Heart J. 2013; 34: 512-519
        • von Haehling S
        • Garfias Macedo T
        • Valentova M
        • et al.
        Muscle wasting as an independent predictor of survival in patients with chronic heart failure.
        J Cachexia Sarcopenia Muscle. 2020; 11: 1242-1249
        • Jackman RW
        • Kandarian SC.
        The molecular basis of skeletal muscle atrophy.
        Am J Physiol Cell Physiol. 2004; 287: C834-C843
        • Aiken CT
        • Kaake RM
        • Wang X
        • Huang L.
        Oxidative stress-mediated regulation of proteasome complexes.
        Mol Cell Proteomics. 2011; 10 (R110 006924)
        • Penna F
        • Ballarò R
        • Beltrà M
        • De Lucia S
        • García Castillo L
        • Costelli P
        The skeletal muscle as an active player against cancer cachexia.
        Front Physiol. 2019; 10
        • Cai D
        • Frantz JD
        • Tawa Jr., NE
        • et al.
        IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.
        Cell. 2004; 119: 285-298
        • Gielen S
        • Sandri M
        • Kozarez I
        • et al.
        Exercise training attenuates MuRF-1 expression in the skeletal muscle of patients with chronic heart failure independent of age: the randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging catabolism study.
        Circulation. 2012; 125: 2716-2727
        • Yoshida T
        • Tabony AM
        • Galvez S
        • et al.
        Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia.
        Int J Biochem Cell Biol. 2013; 45: 2322-2332
        • Sato AY
        • Richardson D
        • Cregor M
        • et al.
        Glucocorticoids induce bone and muscle atrophy by tissue-specific mechanisms upstream of E3 ubiquitin ligases.
        Endocrinology. 2017; 158: 664-677
        • Webster JM
        • Kempen LJAP
        • Hardy RS
        • Langen RCJ.
        Inflammation and skeletal muscle wasting during cachexia.
        Front Physiol. 2020; 11
        • Loncar G
        • Springer J
        • Anker M
        • Doehner W
        • Lainscak M.
        Cardiac cachexia: hic et nunc.
        J Cachexia Sarcopenia Muscle. 2016; 7: 246-260
        • Zhang Y
        • Wang J
        • Wang X
        • et al.
        The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia.
        Am J Clinic Nutr. 2020; 111: 570-579
        • VanderVeen BN
        • Fix DK
        • Carson JA.
        Disrupted skeletal muscle mitochondrial dynamics, mitophagy, and biogenesis during cancer cachexia: a role for inflammation.
        Oxidat Med Cell Longev. 2017; 2017 (3292087-87)
        • Sabbah HN.
        Targeting the mitochondria in heart failure: a translational perspective.
        JACC. 2020; 5: 88-106
        • Rosca MG
        • Hoppel CL.
        Mitochondrial dysfunction in heart failure.
        Heart Fail Rev. 2013; 18: 607-622
        • Sabbah HN
        • Gupta RC
        • Singh-Gupta V
        • Zhang K.
        Effects of elamipretide on skeletal muscle in dogs with experimentally induced heart failure.
        ESC Heart Failure. 2019; 6: 328-335
        • Yoon S
        • Park SJ
        • Han JH
        • et al.
        Caspase-dependent cell death-associated release of nucleosome and damage-associated molecular patterns.
        Cell Death Disease. 2014; 5 (e1494-e94)
        • Filippatos GS
        • Kanatselos C
        • Manolatos DD
        • et al.
        Studies on apoptosis and fibrosis in skeletal musculature: a comparison of heart failure patients with and without cardiac cachexia.
        Int J Cardiol. 2003; 90: 107-113
        • Dinarello CA.
        Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.
        Blood. 2011; 117: 3720-3732
        • Springer J
        • Filippatos G
        • Akashi YJ
        • Anker SD.
        Prognosis and therapy approaches of cardiac cachexia.
        Curr Opin Cardiol. 2006; 21: 229-233
        • Anker SD
        • Ponikowski PP
        • Clark AL
        • et al.
        Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure.
        Eur Heart J. 1999; 20: 683-693
        • Niebauer J
        • Volk HD
        • Kemp M
        • et al.
        Endotoxin and immune activation in chronic heart failure: a prospective cohort study.
        Lancet. 1999; 353: 1838-1842
        • Laird BJ
        • McMillan D
        • Skipworth RJE
        • et al.
        The emerging role of interleukin 1β (IL-1β) in cancer cachexia.
        Inflammation. 2021; 44: 1223-1228
        • Ericsson A
        • Kovács KJ
        • Sawchenko PE.
        A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons.
        J Neurosci. 1994; 14: 897-913
        • Freire PP
        • Cury SS
        • Lopes LO
        • et al.
        Decreased miR-497-5p suppresses IL-6 induced atrophy in muscle cells.
        Cells. 2021; 10: 3527
        • Haehling SV
        • Genth-Zotz S
        • Anker SD
        • Volk HD.
        Cachexia: a therapeutic approach beyond cytokine antagonism.
        Int J Cardiol. 2002; 85: 173-183
        • Ghosh S
        • May MJ
        • Kopp EB.
        NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses.
        Annu Rev Immunol. 1998; 16: 225-260
        • Loppnow H
        • Libby P.
        Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1.
        Cell Immunol. 1989; 122: 493-503
        • Patsalos O
        • Dalton B
        • Leppanen J
        • Ibrahim MAA
        • Himmerich H.
        Impact of TNF-α inhibitors on body weight and BMI: a systematic review and meta-analysis.
        Front Pharmacol. 2020; 11: 481
        • Gaggin HK
        • Belcher AM
        • Gandhi PU
        • Ibrahim NE
        • Januzzi Jr., JL
        Serial echocardiographic characteristics, novel biomarkers and cachexia development in patients with stable chronic heart failure.
        J Cardiovasc Transl Res. 2016; 9: 429-431
        • Nemeth E
        • Rivera S
        • Gabayan V
        • et al.
        IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.
        J Clinic Investig. 2004; 113: 1271-1276
        • Pagani A
        • Nai A
        • Silvestri L
        • Camaschella C.
        Hepcidin and anemia: a tight relationship.
        Front Physiol. 2019; 10
        • Sandek A
        • Swidsinski A
        • Schroedl W
        • et al.
        Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia.
        J Am Coll Cardiol. 2014; 64: 1092-1102
        • Sundaram V
        • Fang JC.
        Gastrointestinal and liver issues in heart failure.
        Circulation. 2016; 133: 1696-1703
        • Anker SD
        • Egerer KR
        • Volk H-D
        • Kox WJ
        • Poole-Wilson PA
        • Coats AJS.
        Elevated soluble CD14 receptors and altered cytokines in chronic heart failure.
        Am J Cardiol. 1997; 79: 1426-1430
        • Valentova M
        • von Haehling S
        • Krause C
        • et al.
        Cardiac cachexia is associated with right ventricular failure and liver dysfunction.
        Int J Cardiol. 2013; 169: 219-224
        • Polsinelli VB
        • Sinha A
        • Shah SJ.
        Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment.
        Curr Heart Fail Rep. 2017; 14: 519-528
        • Arutyunov GP
        • Kostyukevich OI
        • Serov RA
        • Rylova NV
        • Bylova NA.
        Collagen accumulation and dysfunctional mucosal barrier of the small intestine in patients with chronic heart failure.
        Int J Cardiol. 2008; 125: 240-245
        • Anand IS
        • Gupta P.
        Anemia and iron deficiency in heart failure.
        Circulation. 2018; 138: 80-98
        • Sandek A
        • Bauditz J
        • Swidsinski A
        • et al.
        Altered intestinal function in patients with chronic heart failure.
        J Am Coll Cardiol. 2007; 50: 1561-1569
        • Valentova M
        • von Haehling S
        • Bauditz J
        • et al.
        Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure.
        Eur Heart J. 2016; 37: 1684-1691
        • von Haehling S
        • Doehner W
        • Anker SD.
        Nutrition, metabolism, and the complex pathophysiology of cachexia in chronic heart failure.
        Cardiovasc Res. 2007; 73: 298-309
        • van der Wal HH
        • Grote Beverborg N
        • Dickstein K
        • et al.
        Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use.
        Eur Heart J. 2019; 40: 3616-3625
        • Argiles J
        • Madeddu C
        • Moreno C
        • et al.
        CASC-IN: A New Tool to Diagnose Pre-Cachexia in Cancer Patients.
        Annals of Clinical Oncology. 2019; (In press): 1-5https://doi.org/10.31487/j.ACO.2019.04.03
        • Saha S
        • Singh PK
        • Roy P
        • Kakar SS.
        Cardiac cachexia: unaddressed aspect in cancer patients.
        Cells. 2022; 11: 990
        • Clark AL
        • Coats AJS
        • Krum H
        • et al.
        Effect of beta-adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial.
        J Cachexia Sarcopenia Muscle. 2017; 8: 549-556
        • Nagaya N
        • Moriya J
        • Yasumura Y
        • et al.
        Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure.
        Circulation. 2004; 110: 3674-3679
        • Nishie K
        • Yamamoto S
        • Nagata C
        • Koizumi T
        • Hanaoka M.
        Anamorelin for advanced non-small-cell lung cancer with cachexia: systematic review and meta-analysis.
        Lung Cancer. 2017; 112: 25-34
        • Ebner N
        • Anker SD
        • von Haehling S.
        Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference.
        J Cachexia Sarcopenia Muscle. 2020; 11: 274-285
        • Jankowska EA
        • Tkaczyszyn M
        • Suchocki T
        • et al.
        Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials.
        Eur J Heart Fail. 2016; 18: 786-795
        • Rooks D
        • Swan T
        • Goswami B
        • et al.
        Bimagrumab vs optimized standard of care for treatment of sarcopenia in community-dwelling older adults: a randomized clinical trial.
        JAMA Netw Open. 2020; 3 (e2020836-e36)
        • Cheung WW
        • Zheng R
        • Hao S
        • et al.
        The role of IL-1 in adipose browning and muscle wasting in CKD-associated cachexia.
        Sci Rep. 2021; 11: 15141
        • Van Tassell BW
        • Arena RA
        • Toldo S
        • et al.
        Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure.
        PloS one. 2012; 7 (e33438-e38)
        • Okoshi MP
        • Capalbo RV
        • Romeiro FG
        • Okoshi K.
        Cardiac cachexia: perspectives for prevention and treatment.
        Arq Bras Cardiol. 2017; 108: 74-80
        • Borst SE
        • Shuster JJ
        • Zou B
        • et al.
        Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis.
        BMC Med. 2014; 12: 211
        • Fernández-Pombo A
        • Rodríguez-Carnero G
        • Castro AI
        • et al.
        Relevance of nutritional assessment and treatment to counteract cardiac cachexia and sarcopenia in chronic heart failure.
        Clinic Nutr. 2021; 40: 5141-5155
        • Cunha TF
        • Bacurau AVN
        • Moreira JBN
        • et al.
        Exercise training prevents oxidative stress and ubiquitin-proteasome system overactivity and reverse skeletal muscle atrophy in heart failure.
        PloS One. 2012; 7 (e41701-e01)
        • Pineda-Juárez JA
        • Sánchez-Ortiz NA
        • Castillo-Martínez L
        • et al.
        Changes in body composition in heart failure patients after a resistance exercise program and branched chain amino acid supplementation.
        Clin Nutr. 2016; 35: 41-47
        • Azhar G
        • Raza S
        • Pangle A
        • et al.
        Potential beneficial effects of dietary protein supplementation and exercise on functional capacity in a pilot study of individuals with heart failure with preserved ejection fraction.
        Gerontol Geriatr Med. 2020; 62333721420982808
        • von Haehling S
        • Ebner N
        • dos Santos MR
        • Springer J
        • Anker SD.
        Muscle wasting and cachexia in heart failure: mechanisms and therapies.
        Nat Rev Cardiol. 2017; 14: 323-341
        • Mehra MR
        • Lavie CJ
        • Ventura HO
        • Milani RV.
        Fish oils produce anti-inflammatory effects and improve body weight in severe heart failure.
        J Heart Lung Transplant. 2006; 25: 834-838