Cardiac Cachexia: Perspectives for Prevention and Treatment

Abstract

Cachexia is a prevalent pathological condition associated with chronic heart failure. Its occurrence predicts increased morbidity and mortality independent of important clinical variables such as age, ventricular function, or heart failure functional class. The clinical consequences of cachexia are dependent on both weight loss and systemic inflammation, which accompany cachexia development. Skeletal muscle wasting is an important component of cachexia; it often precedes cachexia development and predicts poor outcome in heart failure. Cachexia clinically affects several organs and systems. It is a multifactorial condition where underlying pathophysiological mechanisms are not completely understood making it difficult to develop specific prevention and treatment therapies. Preventive strategies have largely focused on muscle mass preservation. Different treatment options have been described, mostly in small clinical studies or experimental settings. These include nutritional support, neurohormonal blockade, reducing intestinal bacterial translocation, anemia and iron deficiency treatment, appetite stimulants, immunomodulatory agents, anabolic hormones, and physical exercise regimens. Currently, nonpharmacological therapy such as nutritional support and physical exercise are considered central to cachexia prevention and treatment.

Keywords:
Heart Failure; Muscle Wasting; Physical Exercise; Prognosis; Nutrition; Anemia

Resumo

Caquexia é condição patológica prevalente em pacientes com insuficiência cardíaca (IC) associada. Sua ocorrência constitui marcador de gravidade da doença e está associada a aumento da morbidade e mortalidade independentemente de variáveis clínicas importantes como idade, função ventricular ou classe funcional da IC. As consequências clínicas da caquexia dependem tanto da perda de peso como da inflamação sistêmica que acompanha seu desenvolvimento. Perda da musculatura esquelética é importante componente da caquexia; ela frequentemente precede o desenvolvimento desta condição e está associada a mau prognóstico da IC. A caquexia afeta vários órgãos e sistemas. Sua origem é multifatorial; como os mecanismos fisiopatológicos envolvidos em seu desenvolvimento não estão completamente entendidos, há grande dificuldade no desenvolvimento de terapia específica para a prevenção e tratamento. Estratégias para a prevenção visam, principalmente, a preservação da massa muscular. Diferentes opções de tratamento têm sido descritas, a maioria delas avaliada em estudos experimentais ou pequenos estudos clínicos. Estas incluem suporte nutricional, bloqueio de sistemas neuro-hormonais, redução de translocação bacteriana intestinal, tratamento da anemia e ferrodeficiência, estimulantes de apetite, agentes imunomodulatórios, hormônios anabólicos, e diferentes programas de exercícios físicos. Atualmente, a terapia não farmacológica como o suporte nutricional e exercícios físicos tem sido considerada de grande importância na prevenção e tratamento da caquexia associada à IC.

Palavras-chave
Insuficiência Cardíaca; Perda de Massa Muscular; Exercício Físico; Prognóstico; Nutrição; Anemia

Introduction

Heart failure is an important public health issue due to a high prevalence, severity of clinical manifestations and poor prognosis. Statistical data from the United States estimate that 5.7 million Americans over 20 years of age have heart failure; this is expected to increase by approximately 46% between 2012 and 2030, resulting in over 8 million adults with heart failure.¹

Heart failure is caused by structural and functional abnormalities in the heart leading to impaired ventricular ejection and/or filling capacity. In Brazil, the main causes of heart failure are myocardial ischemia, systemic arterial hypertension, dilated cardiomyopathy and Chagas' disease, and valve disease.² Following cardiac injury, the ensuing molecular, structural, and functional ventricular changes are known as cardiac remodeling. This process is accompanied by cardiac and systemic neurohormonal and inflammatory activation, which adversely affects the heart in a vicious cycle and jeopardizes different organs and systems.³ In recent decades, it has become clear that pathological changes involve not only the cardiovascular system, but also the renal, neuroendocrinological, immunological, hematologic, gastrointestinal, and musculoskeletal systems, as well as the nutritional status. Currently, experimental and clinical studies have focused on the physiopathology of heart failure-related systemic complications in order to establish treatments to improve quality of life and increase survival.

Cachexia is a prevalent and important pathological condition associated with chronic heart failure. Its occurrence predicts reduced survival, independent of relevant variables such as age, heart failure functional class, ejection fraction, and physical capacity.⁴ We evaluate studies on heart failure-induced cachexia and discuss different therapies for its prevention and treatment.

Cardiac cachexia definition

Cachexia has been defined as at least 5% edema-free body weight loss in the previous 12 months (or a body mass index < 20 kg/m²) in patients with chronic illness and at least three of the following clinical or laboratory criteria: decreased muscle strength, fatigue, anorexia, low fat-free mass index and abnormal biochemistry characterized by increased inflammatory markers [C-reactive protein, interleukin (IL)-6], anemia (Hb < 12 g/dL), or low serum albumin (< 3.2 g/dL).⁵ As heart failure is an inflammatory disease, Anker et al.⁶ proposed that cardiac cachexia should be diagnosed when body weight loss is > 6% regardless of other criteria and in the absence of other severe diseases. More recently, investigators have used a body weight loss cutoff > 5% to characterize cardiac cachexia.^7,8 It should be pointed out that cachexia is different from malnutrition or anorexia, which can both easily be reversed with adequate nutrition.⁵ Currently, several biomarkers have been studied to help diagnose cardiac cachexia.⁹ Muscle wasting is an important component of cachexia. It often precedes cachexia development and may also predict poor outcome in heart failure.¹⁰ Differently from cachexia, muscle loss diagnosis depends on the laboratory evaluation of muscle mass, such as dual energy X-ray absorptiometry (DEXA), computed tomography and magnetic resonance imaging.¹¹ Muscle wasting may also be suggested by poor performance during spiroergometry, 6-min walking test, gait speed, or handgrip strength.¹¹

The importance of cachexia in heart failure prognosis became more evident after the description of the reverse epidemiology of obesity in this condition. In healthy people, increased body mass index is associated with an elevated risk of developing cardiovascular disease. However, body mass index was positively correlated with survival in heart failure patients.¹² In a meta-analysis of nine observational studies, mortality was lower in overweight and obese heart failure patients.¹³ The mechanisms involved in both the obesity paradox and the cachexia-induced worse prognosis are not completely clear.¹⁴

Cardiac cachexia prevalence varies between 8 and 42% according to cachexia definition and the study population.^6,7,15 Anker et al.⁶ observed that 34% of heart failure outpatients had a ≥ 6% body weight loss during 48 months of follow-up. More recently, in optimally-treated nondiabetic outpatients, a > 5% body weight loss was observed in 10.5%.⁷

The etiology of heart failure-associated cachexia is multifactorial and the underlying pathophysiological mechanisms are not well established.¹⁶ Important factors include food intake reduction, gastrointestinal abnormalities, immunological and neurohormonal activation and an imbalance between anabolic and catabolic processes.^16,17

Clinical consequences of cachexia

The clinical consequences of cachexia depend on both weight loss and systemic inflammation, which accompany cachexia development. Severe body weight loss, even in the absence of systemic inflammation, is associated with deleterious effects on most organs and systems. Tissue loss from three compartments, lean tissue, fat mass, and bones, is usually found.⁷ In skeletal muscles, an imbalance between protein synthesis and breakdown leads to molecular changes and muscle atrophy, with decreased strength and daily activity impairment.^18-23

The cardiac consequences of cachexia have been studied in heart disease-free conditions, such as cancer and undernutrition.^24-30 In cachectic individuals, left ventricular mass correlated with lean body mass, showing that the heart is subjected to similar consequences to those in lean tissue during cachexia.³¹ In experimental animals, cancer cachexia induced cardiac dysfunction and molecular changes characteristic of the pathologic remodeling process with reduced anabolic pathway signaling.^24,25 We observed that severe food restriction induces mild ultrastructural, morphological, and functional changes in normal rat hearts, which are exacerbated by hemodynamic overload in hypertensive rats.^32-37 Therefore, the occurrence of cachexia can further impair cardiac changes and heart failure in a fatal vicious cycle. Cachexia can also exacerbate heart failure-associated anemia and gastrointestinal changes.³⁸

Cachexia prevention and treatment

As cardiac cachexia is multifactorial, it has been difficult to develop a specific therapy for its prevention and treatment.¹¹ Since skeletal muscle wasting can precede cachexia, preventive strategies have been largely directed towards muscle mass preservation.³⁹ Different options have been described, mostly evaluated in small clinical studies or experimental settings. These include nutritional support, neurohormonal blockade, reduced intestinal bacterial translocation, anemia and iron deficiency treatment, appetite stimulants, immunomodulatory agents, anabolic hormones, and physical exercise regimes (Table 1).¹¹ Currently, nonpharmacological therapy such as nutritional support and physical exercise has been considered as the basis for cachexia prevention and treatment.⁴⁰

Table 1
Cardiac cachexia: perspectives for prevention and treatment

Nonpharmacological approach

Nutritional support

Physical exercise

Drug therapy approach

Treatment clinically useful

Neurohormonal blockade

Reduction in intestinal bacterial translocation by peripheral edema control

Anemia and iron deficiency correction

Experimental use only

Supplementation of essential amino acids

Supplementation of branched-chain amino acids

Appetite stimulants

Immunomodulatory agents (pentoxyphylline, thalidomide, statins, methotrexate, N-acetylcysteine, T-cell activation inhibitors, chemokine antagonists, interleukin-10, interleukin-1 receptor antagonists)

Anabolic hormones (testosterone, growth hormone release-inducing, growth hormone)

Several mechanisms: myostatin inhibitors and antagonists, bortezomide, lipopolysaccharide bioactivity inhibitors, and melanocortin blockers

Nutritional support

Non-obese patients with stable heart failure often have inadequate food intake.⁴¹ Therefore, nutritional support is recommended to obtain and maintain a body weight within or a little below the normal range without edema. Currently, there is no specific recommendation for protein and energy intake. The ingestion of 35 kcal/kg/day was shown to be safe and effective in increasing lean mass in heart failure patients.⁴² Some authors have recommended a caloric intake of at least 31.8 kcal/kg/day.⁴¹ Nutritional support should be started with small amounts and slowly increased until desired body weight is reached. Excess energy intake increases catecholamine and insulin plasma concentrations causing physiological stress. An increase in insulin levels induces renal sodium and water reabsorption and may decompensate cardiac failure. Therefore, patients should be advised to evaluate their body weight daily and tailor diuretic therapy. Protein intake should follow recommendations for healthy people and may be increased in cases of protein loss by intestinal malabsorption or nephropathy. However, a small trial showed that high-caloric protein-rich oral nutritional supplement improved body weight and reduced inflammatory markers.⁴³ Sodium intake depends on heart failure functional class, being more restricted (0.5 to 2 g/day) in severe cases; this is when patients need to be educated on food sodium content. Chronic and vigorous use of diuretics can deplete potassium and magnesium levels. With increased carbohydrates and amino acids intake and increased insulin levels, there is a shift in potassium, magnesium and phosphorus from extracellular to intracellular compartments, thus decreasing plasma concentrations of these electrolytes which can induce cardiac arrhythmias and sudden death.

There is no specific recommendation for micronutrients in heart failure. Reduced food intake and chronic use of diuretics can cause water-soluble vitamin deficiency. Thiamine needs particular attention as a deficiency may impair cardiac function.⁴⁴ Intestinal malabsorption can reduce plasma levels of the soluble vitamins A, D, E, and K.⁴⁴ As liver congestion and ascites cause food intake intolerance, meals should be frequent and small. It should be stressed that, despite the importance of nutritional support, it has not been established whether adequate protein-energy intake can reverse nutritional status in chronic heart failure.⁴⁵ Furthermore, increased food intake may compensate some weight loss, but it can change tissue distribution towards increased fat mass, particularly when muscle loss is present.⁴⁶ Therefore, to preserve or recover muscle mass, nutritional support should be combined with physical exercise.

Recent small studies have suggested that alterations in specific diet components may be useful in cardiac cachexia. For example, supplements of essential amino acids improved nutritional and metabolic status in most muscle-depleted heart failure patients.⁴⁵ Supplementation of branched-chain amino acids, which consist of leucine, isoleucine, and valine, preserved body weight, skeletal muscle mass, and cardiac function in rats;⁴⁷ however, it failed to benefit heart failure patients.⁴⁸

Neurohormonal activation blockade

Chronic heart failure is characterized by sustained cardiac and systemic activation of the renin-angiotensin-aldosterone and adrenergic nervous systems which, in the long term, impairs ventricular remodeling. Therefore, blockade of these systems is recommended for all heart failure patients with reduced ejection fraction.^2,49 The heart failure control with neurohormonal blockade can reverse cachexia independently of nutritional support.

However, neurohormonal activation is also directly involved in skeletal muscle atrophy. The effects of angiotensin II can be prevented by angiotensin-converting enzyme inhibitors (ACEi) and angiotensin 1 receptor blockers. More recently, angiotensin II has been shown to play a role in cachexia and skeletal muscle wasting through different mechanisms such as increased oxidative stress and protein breakdown; impaired energy balance; reduced appetite via alteration in orexigenic/anorexigenic neuropeptides in the hypothalamus; and inhibition of satellite cell function and muscle regeneration.^50,51 Administration of ACEi enalapril decreased the risk of weight loss in heart failure patients.⁶ One may argue that as angiotensin II antagonism improves cardiac remodeling and ventricular function, it would also reduce the risk for cachexia development. Thus, neurohormonal blockade was also examined in cancer cachexia. In tumor-bearing rats, angiotensin and aldosterone antagonism as well as adrenergic nervous system blockade attenuated body weight and lean mass loss.²⁵ In a phase III clinical trial, ACEi imidapril prevented weight loss in patients with cachexia caused by non-small cell lung cancer and colorectal cancer but not by pancreatic cancer. When data were combined however, weight loss prevention did not reach statistical significance.⁵¹ Future studies are needed to elucidate the role of neurohormonal blockade in different causes of cachexia.

Reduction in intestinal bacterial translocation

Heart failure patients with peripheral edema present increased intestine wall thickness, which suggests bowel wall edema.³⁸ Among echocardiographic parameters, the combination of right ventricular dysfunction and elevated right atrial pressure provided the best discrimination between cachectic and non-cachectic patients.⁵² Furthermore, cardiac cachexia was associated with intestinal congestion irrespective of heart failure stage and cardiac function.⁵² Heart failure patients also have a reduction in intestinal blood flow and an increase in juxtamucosal bacterial growth.⁵³ These abnormalities lead to intestinal bacterial translocation and systemic immune activation.^53,54 Bacterial endotoxins, also known as lipopolysaccharides, are potent inducers of pro-inflammatory substances such as tumor necrosis factor (TNF)-α. As intensive diuretic therapy normalized increased endotoxin levels in heart failure patients with peripheral edema,⁵⁴ patients should have as little edema as possible by using one or a combination of diuretics.⁴⁹ Despite experimental studies showing antibiotic therapy decreases intestinal bacterial translocation, it is not established whether microflora modulation is safe or useful in reducing systemic immune activation in heart failure. Therefore, this approach is not currently recommended.⁵⁵

Anemia and iron deficiency treatment

The prevalence of anemia in heart failure ranges from 4% to 55%, according to study population and anemia definition.⁵⁶ Anemia is associated with increased mortality, hospitalization, and impaired quality of life.⁵⁷ Anemia etiology in heart failure is multifactorial. Iron deficiency is present in about half of heart failure patients, independent of the presence of anemia.⁵⁶ Both anemia and iron deficiency are associated with reduced exercise tolerance.⁵⁸ As decreased exercise capacity is related to a reduced skeletal muscle mass, anemia and iron deficiency may be involved in cachexia development. Diagnostic evaluation for reversible causes of anemia and subsequent treatment is appropriate in all patients. Currently, several heart associations suggest that iron deficiency should be routinely checked in all heart failure patients and corrected if present.⁵⁶ Intravenous iron preparations are safe and effective in treating iron deficiency;⁵⁸ little information is available on the effectiveness of oral iron.⁵⁶ Intravenous iron correction of iron deficiency was associated with improved functional status.⁵⁹ As erythropoiesis stimulating agent darbepoetin alpha failed to improve clinical outcomes in heart failure patients with mild-to-moderate anemia,⁶⁰ this class of drug is not recommended for treating heart failure-associated anemia.

Perspectives for future treatment of cachexia

Several pharmacological agents have been tested in experimental and clinical settings for preventing and treating cardiac cachexia. However, they currently represent perspectives for the future and are not recommended for clinical use.

Appetite loss is a common finding in cardiac cachexia and its origin is multifactorial.¹⁵ Although appetite stimulants such as megestrol acetate have been used in other cachectic conditions, they are not approved for cardiac cachexia.

As previously stated, chronic cardiac failure is followed by immunologic activation, which plays an important role in cachexia development. Therefore, several immunomodulatory agents have been tested in heart failure. Tumor necrosis factor (TNF)-α antagonists etanercept and infliximab were tested in large clinical trials with neutral or negative results.⁶¹ Pentoxyphylline and thalidomide, also considered immunomodulatory agents, were used in small trials with neutral or favorable results.^62,63 Other immunomodulatory drugs such as statins, methotrexate, N-acetylcysteine, T-cell activation inhibitors, chemokine antagonists, IL-10, and IL-1 receptor antagonists have been tested in experimental studies.^19,64

Anabolic hormones have also been examined to preserve and/or increase muscle mass. Testosterone levels decrease with age; this phenomenon being faster in heart failure men than in their healthy male counterparts.⁶⁵ Low concentration of testosterone was related to increased risk of death, independently of left ventricular function or functional capacity.^39,65 In skeletal muscle, testosterone increases protein synthesis, reduces protein breakdown, and stimulates proliferation and differentiation of satellite cells, thus increasing muscle mass and strength, and improving exercise capacity.³⁹ Therefore, androgen deficiency may be involved in the imbalance between anabolic and catabolic processes and contribute to heart failure-induced muscle wasting and cachexia.⁶⁵ Testosterone supplementation was evaluated in small randomized double-blind studies including elderly men⁶⁶ and women⁶⁷ with heart failure. As testosterone improved functional capacity and muscle strength, it was hypothesized that it could be safe and useful in heart failure and cardiac cachexia.

Growth hormone release-inducing (Ghrelin) increases adiposity and food intake by modulating neural circuits that control food intake, energy expenditure, and reward.⁶⁸ Ghrelin has been evaluated in small trials in different cachectic conditions.¹⁵ In heart failure, repeated Ghrelin administration improved exercise capacity and muscle wasting, suggesting that Ghrelin and its receptor agonist anamorelin may be an attractive approach for future investigation.^68,69 Growth hormone (GH) also have the potential to improve muscle mass and functional capacity.⁷⁰ However, as their effects are not completely established in heart failure patients,^{71 72} additional research is needed to clarify the role of GH in cardiac failure and cachexia.

Currently, several drugs such as myostatin inhibitors and antagonists, bortezomide (an ubiquitin-proteasome route inhibitor), lipopolysaccharide bioactivity inhibitors, and melanocortin blockers have been investigated with the purpose of preserving and/or increasing muscle mass in cardiac cachexia.^9,20,22

Physical Exercise

Physical exercise is the most promising option for treating muscle wasting in several diseases. Current heart failure guidelines strongly recommend regular physical exercise for stable patients to prevent and/or attenuate cardiac remodeling and skeletal muscle alterations.^2,49,73 Clinical and experimental studies have shown that aerobic exercise improves cardiac remodeling and ventricular function, and increases functional capacity and quality of life.^74-76 In skeletal muscle, exercise training reduces oxidative stress, activation of the ubiquitin-proteasome system, expression of myostatin and proinflammatory cytokines, sympathetic nerve activity and peripheral vasoconstriction, reestablishes expression of proteins involved in sarcoplasmic calcium handling, and prevents capillary rarefaction and atrophy.^77-79

Other exercise modalities have also shown promising results in heart failure. For example, a resistance exercise program improved functional capacity⁴⁸ and a combination of hydrotherapy with endurance training improved exercise tolerance and hemodynamic profile of heart failure patients.⁸¹ Additionally, high-intensity aerobic exercise was safe and superior to moderate-intensity aerobic training in increasing maximal oxygen consumption.⁸² Therefore, additional studies are needed to establish the best training protocol relating to exercise type, intensity, duration, and frequency to improve outcomes in cardiac cachexia.

Conclusion

Cachexia plays an important role in morbidity and mortality in heart failure patients. Understanding the pathophysiological mechanisms that cause cachexia is an essential step to developing pharmacological and non-pharmacological strategies aimed at effectively preventing and treating heart failure-induced cachexia before significant body weight and muscle wasting occurs. Currently, nonpharmacological therapy such as nutritional support and physical exercise are the basis for cachexia prevention and treatment.

• Sources of Funding
  This study was funded by FAPESP and CNPq.
• Study Association
  This study is not associated with any thesis or dissertation work.

Acknowledgement

We are grateful to Colin Edward Knaggs for English editing. Financial support was provided by CNPq (306857/2012-0, 306845/2012-1, and 479085/2013-7), FAPESP (2012/50512-5, 2014/21972-3), CAPES, and PROPe, UNESP.

References

• ¹
  Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Executive Summary: Heart Disease and Stroke Statistics--2016 Update: A Report From the American Heart Association. Circulation. 2016;133(4):447-54.
• ²
  Bocchi EA, Marcondes-Braga FG, Bacal F, Ferraz AS, Albuquerque D, Rodrigues D, et al. [Updating of the Brazilian guideline for chronic heart failure - 2012]. Arq Bras Cardiol. 2012;98(1 Suppl 1):1-33.
• ³
  Mann DL. Pathophysiology of heart failure. In: Bonow RO, Mann DL, Zipes DP, Libby P, Braunwald E. (eds.). Braunwald's heart disease. Philadelphia: Elsevier Saunders; 2012. p. 487-504.
• ⁴
  Rossignol P, Masson S, Barlera S, Girerd N, Castelnovo A, Zannad F, et al; GISSI-HF and Val-HeFT Investigators. Loss in body weight is an independent prognostic factor for mortality in chronic heart failure: insights from the GISSI-HF and VAL-HEFT trials. Eur J Heart Fail. 2015;17(4):424-33.
• ⁵
  Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr. 2008;27(6):793-9.
• ⁶
  Anker SD, Negassa A, Coats AJ, Afzal R, Poole-Wilson PA, Cohn JN, 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(9363):1077-83.
• ⁷
  Christensen HM, Kistorp C, Schou M, Keller N, Zerahn B, Frystyk J, et al. Prevalence of cachexia in chronic heart failure and characteristics of body composition and metabolic status. Endocrine. 2013;43(3):626-34.
• ⁸
  Trullas JC, Formiga F, Montero M, Carrera-Izquierdo M, Grau-Amorós J, Chivite-Guillén D, et al; RICA Investigators. Impact of weight loss on mortality in chronic heart failure: findings from the RICA Registry. Int J Cardiol. 2013;168(1):306-11.
• ⁹
  Martins T, Vitorino R, Amado F, Duarte JA, Ferreira R. Biomarkers for cardiac cachexia: reality or utopia. Clin Chim Acta. 2014;436:323-8.
• ¹⁰
  Fulster S, Tacke M, Sandek A, Ebner N, Tschope C, Doehner W, et al. Muscle wasting in patients with chronic heart failure: results from the studies investigating comorbidities aggravating heart failure (SICA-HF). Eur Heart J. 2013;34(7):512-9.
• ¹¹
  Ebner N, Elsner S, Springer J, von Haehling S. Molecular mechanisms and treatment targets of muscle wasting and cachexia in heart failure: an overview. Curr Opin Support Palliat Care. 2014;8(1):15-24.
• ¹²
  Kalantar-Zadeh K, Block G, Horwich T, Fonarow GC. Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol. 2004;43(8):1439-44.
• ¹³
  Oreopoulos A, Padwal R, Kalantar-Zadeh K, Fonarow GC, Norris CM, McAlister FA. Body mass index and mortality in heart failure: a meta-analysis. Am Heart J. 2008;156(1):13-22.
• ¹⁴
  Lavie CJ, De Schutter A, Alpert MA, Mehra MR, Milani RV, Ventura HO. Obesity paradox, cachexia, frailty, and heart failure. Heart Fail Clin. 2014;10(2):319-26.
• ¹⁵
  von Haehling S, Anker SD. Treatment of cachexia: an overview of recent developments. Int J Cardiol. 2015;184:736-42.
• ¹⁶
  Rahman A, Jafry S, Jeejeebhoy K, Nagpal AD, Pisani B, Agarwala R. Malnutrition and cachexia in heart failure. JPEN J Parenter Enteral Nutr. 2016;40(4):475-86.
• ¹⁷
  Okoshi MP, Romeiro FG, Paiva SA, Okoshi K. Heart failure-induced cachexia. Arq Bras Cardiol. 2013;100(5):476-82.
• ¹⁸
  Martinez PF, Okoshi K, Zornoff LA, Carvalho RF, Oliveira Junior SA, Lima AR, et al. Chronic heart failure-induced skeletal muscle atrophy, necrosis, and myogenic regulatory factors changes. Med Sci Monit. 2010;16(12):BR374-83.
• ¹⁹
  Martinez PF, Bonomo C, Guizoni DM, Junior SA, Damatto RL, Cezar MD, et al. Influence of N-acetylcysteine on oxidative stress in slow-twitch soleus muscle of heart failure rats. Cell Physiol Biochem. 2015;35(1):148-59.
• ²⁰
  Lima AR, Martinez PF, Okoshi K, Guizoni DM, Zornoff LA, Campos DH, et al. Myostatin and follistatin expression in skeletal muscles of rats with chronic heart failure. Int J Exp Path. 2010;91(1):54-62.
• ²¹
  Lima AR, Martinez PF, Damatto RL, Cezar MD, Guizoni DM, Bonomo C, et al. Heart failure-induced diaphragm myopathy. Cell Physiol Biochem. 2014;34(2):333-45.
• ²²
  Damatto RL, Martinez PF, Lima AR, Cezar MD, Campos DH, Oliveira SA, et al. Heart failure-induced skeletal myopathy in spontaneously hypertensive rats. Int J Cardiol. 2013;167(3):698-703.
• ²³
  Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, et al. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation. 1992;85(4):1364-73.
• ²⁴
  Tian M, Asp ML, Nishijima Y, Belury MA. Evidence for cardiac atrophic remodeling in cancer-induced cachexia in mice. Int J Oncol. 2011;39(5):1321-6.
• ²⁵
  Springer J, Tschirner A, Haghikia A, von Haehling S, Lal H, Grzesiak A, et al. Prevention of liver cancer cachexia-induced cardiac wasting and heart failure. Eur Heart J. 2014;35(14):932-41.
• ²⁶
  Sugizaki MM, Carvalho RF, Aragon FF, Padovani CR, Okoshi K, Okoshi MP, et al. Myocardial dysfunction induced by food restriction is related to morphological damage in normotensive middle-aged rats. J Biomed Sci. 2005;12(4):641-9.
• ²⁷
  Okoshi K, Matsubara LS, Okoshi MP, Cicogna AC, Fioretto JR, Padovani CR, et al. Food restriction-induced myocardial dysfunction demonstrated by the combination of in vivo and in vitro studies. Nutr Res. 2002;22(11):1353-64.
• ²⁸
  Gut AL, Okoshi MP, Padovani CR, Aragon FF, Cicogna AC. Myocardial dysfunction induced by food restriction is related to calcium cycling and beta-adrenergic system changes. Nutr Res. 2003;23(7):911-9.
• ²⁹
  Fioretto JR, Queiroz SS, Padovani CR, Matsubara LS, Okoshi K, Matsubara BB. Ventricular remodeling and diastolic myocardial dysfunction in rats submitted to protein-calorie malnutrition. Am J Physiol Heart Circ Physiol. 2002;282(4):H1327-33.
• ³⁰
  Sugizaki MM, Leopoldo AS, Okoshi MP, Bruno A, Conde SJ, Lima-Leopoldo AP, et al. Severe food restriction induces myocardial dysfunction related to Serca2 activity. Can J Physiol Pharmacol. 2009;87(9):666-73.
• ³¹
  Molfino A, Papa A, Gasperini-Zacco ML, Muscaritoli M, Amoroso A, Cascino A, et al. Left ventricular mass correlates with lean body mass in patients with disease-associated wasting. J Cachexia Sarcopenia Muscle. 2014;5(3):251-2.
• ³²
  Okoshi MP, Okoshi K, Pai VD, Pai-Silva MD, Matsubara LS, Cicogna AC. Mechanical, biochemical, and morphological changes in the heart from chronic food restricted rats. Can J Physiol Pharmacol. 2001;79(9):754-60.
• ³³
  Cicogna AC, Padovani CR, Okoshi K, Matsubara LS, Aragon FF, Okoshi MP. The influence of temporal food restriction on the performance of isolated cardiac muscle. Nutr Res. 2001;21(4):639-48.
• ³⁴
  Cicogna AC, Padovani CR, Okoshi K, Aragon FF, Okoshi MP. Myocardial function during chronic food restriction in isolated hypertrophied cardiac muscle. Am J Med Sci. 2000;320(4):244-8.
• ³⁵
  Okoshi K, Fioretto JR, Okoshi MP, Cicogna AC, Aragon FF, Matsubara LS, et al. Food restriction induces in vivo ventricular dysfunction in spontaneously hypertensive rats without impairment of in vitro myocardial contractility. Braz J Med Biol Res. 2004;37(4):607-13.
• ³⁶
  Okoshi MP, Okoshi K, Matsubara LS, Pai-Silva MD, Gut AL, Padovani CR, et al. Myocardial remodeling and dysfunction are induced by chronic food restriction in spontaneously hypertensive rats. Nutr Res. 2006;26(11):567-72.
• ³⁷
  Gut AL, Sugizaki MM, Okoshi MP, Carvalho RF, Pai-Silva MD, Aragon FF, et al. Food restriction impairs myocardial inotropic response to calcium and beta-adrenergic stimulation in spontaneously hypertensive rats. Nutr Res. 2008;28(10):722-7.
• ³⁸
  Romeiro FG, Okoshi K, Zornoff LA, Okoshi MP. Gastrointestinal changes associated to heart failure. Arq Bras Cardiol. 2012;98(3):273-7.
• ³⁹
  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(4):287-96.
• ⁴⁰
  Alves CR, da Cunha TF, da Paixão NA, Brum PC. Aerobic exercise training as therapy for cardiac and cancer cachexia. Life Sci. 2015;125:9-14.
• ⁴¹
  Aquilani R, Opasich C, Verri M, Boschi F, Febo O, Pasini E, et al. Is nutritional intake adequate in chronic heart failure patients? J Am Coll Cardiol. 2003;42(7):1218-23.
• ⁴²
  Heymsfield SB, Casper K. Congestive heart failure: clinical management by use of continuous nasoenteric feeding. Am J Clin Nutr. 1989;50(3):539-44.
• ⁴³
  Rozentryt P, von Haehling S, Lainscak M, Nowak JU, Kalantar-Zadeh K, Polonski L, et al. The effects of a high-caloric protein-rich oral nutritional supplement in patients with chronic heart failure and cachexia on quality of life, body composition, and inflammation markers: a randomized, double-blind pilot study. J Cachexia Sarcopenia Muscle. 2010;1(1):35-42.
• ⁴⁴
  Krim SR, Campbell P, Lavie CJ, Ventura H. Micronutrients in chronic heart failure. Curr Heart Fail Rep. 2013;10(1):46-53.
• ⁴⁵
  Aquilani R, Opasich C, Gualco A, Verri M, Testa A, Pasini E, et al. Adequate energy-protein intake is not enough to improve nutritional and metabolic status in muscle-depleted patients with chronic heart failure. Eur J Heart Fail. 2008;10(11):1127-35.
• ⁴⁶
  Ebner N, Springer J, Kalantar-Zadehb K, Lainscakc M, Doehner W, Anker SD, et al. Mechanism and novel therapeutic approaches to wasting in chronic disease. Maturitas. 2013;75(3):199-206.
• ⁴⁷
  Tanada Y, Shioi T, Kato T, Kawamoto A, Okuda J, Kimura T. Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats. Life Sci. 2015;137:20-7.
• ⁴⁸
  Pineda-Juarez JA, Sanchez-Ortiz NA, Castillo-Martinez L, Orea-Tejeda A, Cervantes-Gaytan R, Keirns-Davis C, 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(1):41-7.
• ⁴⁹
  Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation / American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):1810-52.
• ⁵⁰
  Du Bois P, Pablo Tortola C, Lodka D, Kny M, Schmidt F, Song K, et al. Angiotensin II induces skeletal muscle atrophy by activating TFEB-mediated MuRF1 expression. Circ Res. 2015;117(5):424-36.
• ⁵¹
  Yoshida T, Delafontaine P. Mechanisms of cachexia in chronic disease states. Am J Med Sci. 2015;350(4):250-6.
• ⁵²
  Valentova M, von Haehling S, Bauditz J, Doehner W, Ebner N, Bekfani T, 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(21):1684-91.
• ⁵³
  Sandek A, Swidsinski A, Schroedl W, Watson A, Valentova M, Herrmann R, 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(11):1092-102.
• ⁵⁴
  Azhar G, Wei JY. New approaches to treating cardiac cachexia in the older patient. Curr Cardiovasc Risk Rep. 2013;7(6):480-4.
• ⁵⁵
  Sandek A, Anker SD, von Haehling S. The gut and intestinal bacteria in chronic heart failure. Curr Drug Metab. 2009;10(1):22-8.
• ⁵⁶
  Silverberg DS, Wexler D, Schwartz D. Is correction of iron deficiency a new addition to the treatment of the heart failure? Int J Mol Sci. 2015;16(6):14056-74.
• ⁵⁷
  Tang YD, Katz SD. Anemia in chronic heart failure: prevalence, etiology, clinical correlates, and treatment options. Circulation. 2006;113(20):2454-61.
• ⁵⁸
  McDonagh T, Macdougall IC. Iron therapy for the treatment of iron deficiency in chronic heart failure: intravenous or oral? Eur J Heart Fail. 2015;17(3):248-62.
• ⁵⁹
  Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436-48.
• ⁶⁰
  Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, et al; RED-HF Committees; RED-HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368(13):1210-9.
• ⁶¹
  Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004;109(13):1594-602.
• ⁶²
  Shaw SM, Shah MK, Williams SG, Fildes JE. Immunological mechanisms of pentoxifylline in chronic heart failure. Eur J Heart Fail. 2009;11(2):113-8.
• ⁶³
  Fildes JE, Shaw SM, Yonan N, Williams SG. The immune system and chronic heart failure: is the heart in control? J Am Coll Cardiol. 2009;53(12):1013-20.
• ⁶⁴
  El Desoky ES. Drug therapy of heart failure: an immunologic view. Am J Ther. 2011;18(5):416-25.
• ⁶⁵
  Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, et al. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006;114(17):1829-37.
• ⁶⁶
  Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure: a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol. 2009;54(10):919-27.
• ⁶⁷
  Iellamo F, Volterrani M, Caminiti G, Karam R, Massaro R, Fini M, et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol. 2010;56(16):1310-6.
• ⁶⁸
  Muller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. Mol Metab. 2015;4(6):437-60.
• ⁶⁹
  Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, et al. Effects of Ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation. 2004;110(24):3674-9.
• ⁷⁰
  Santos DP, Okoshi K, Moreira VO, Seiva FR, Almeida FL, Padovani CR, et al. Growth hormone attenuates skeletal muscle changes in experimental chronic heart failure. Growth Horm IGF Res. 2010;20(2):149-55.
• ⁷¹
  Osterziel KJ, Strohm O, Schuler J, Friedrich M, Hanlein D, Willenbrock R, et al. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. 1998;351(9111):1233-7.
• ⁷²
  Isgaard J, Bergh CH, Caidahl K, Lomsky M, Hjalmarson A, Bengtsson BA. A placebo-controlled study of growth hormone in patients with congestive heart failure. Eur Heart J. 1998;19(11):1704-11.
• ⁷³
  McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):803-69. Erratum in: Eur J Heart Fail. 2013;15(3):361-2.
• ⁷⁴
  Flynn KE, Pina IL, Whellan DJ, Lin L, Blumenthal JA, Ellis SJ, et al. Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA. 2009;301(14):1451-9. Erratum in: JAMA. 2009;302(21):2322.
• ⁷⁵
  Giannuzzi P, Temporelli PL, Corra U, Tavazzi L; ELVD-CHF Study Group. Antiremodeling effect of long-term exercise training in patients with stable chronic heart failure: results of the exercise in left ventricular dysfunction and chronic heart failure (ELVD-CHF) trial. Circulation. 2003;108(5):554-9.
• ⁷⁶
  Pagan LU, Damatto RL, Cezar MD, Lima AR, Bonomo C, Campos DH, et al. Long-term low intensity physical exercise attenuates heart failure development in aging spontaneously hypertensive rats. Cell Physiol Biochem. 2015;36(1):61-74.
• ⁷⁷
  Gomes MJ, Martinez PF, Campos DH, Pagan LU, Bonomo C, Lima AR, et al. Beneficial effects of physical exercise on functional capacity and skeletal muscle oxidative stress in rats with aortic stenosis-induced heart failure. Oxid Med Cell Longev. 2016;2016:8695716.
• ⁷⁸
  Souza RW, Piedade WP, Soares LC, Souza PA, Aguiar AF, Vechetti-Junior IJ, et al. Aerobic exercise training prevents heart failure-induced skeletal muscle atrophy by anti-catabolic, but not anabolic actions. PLoS One. 2014;9(10):e110020.
• ⁷⁹
  Negrao CE, Middlekauff HR, Gomes-Santos IL, Antunes-Correa LM. Effects of exercise training on neurovascular control and skeletal myopathy in systolic heart failure. Am J Physiol Heart Circ Physiol. 2015;308(8):H792-802.
• ⁸⁰
  Bueno CR Jr, Ferreira JC, Pereira MG, Bacurau AV, Brum PC. Aerobic exercise training improves skeletal muscle function and Ca²⁺ handling-related protein expression in sympathetic hyperactivity-induced heart failure. J Appl Physiol (1985). 2010;109(3):702-9.
• ⁸¹
  Caminiti G, Volterrani M, Marazzi G, Cerrito A, Massaro R, Sposato B, et al. Hydrotherapy added to endurance training versus endurance training alone in elderly patients with chronic heart failure: a randomized pilot study. Int J Cardiol. 2011;148(2):199-203.
• ⁸²
  Wisloff U, Stoylen A, Loennechen JP, Bruvold M, Rognmo O, Haram PM, et al. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation. 2007;115(24):3086-94.

Publication Dates

• Publication in this collection
  27 Oct 2016
• Date of issue
  Jan 2017

History

• Received
  05 Feb 2016
• Reviewed
  13 May 2016
• Accepted
  23 May 2016