Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC JdxHDwtW8KLsGFcN9NvgMhM S0066-782X2017000100074 10.5935/abc.20160142 S0066-782X2016005025101 Review Article Cardiac Cachexia: Perspectives for Prevention and Treatment Okoshi Marina Politi 1 Capalbo Rafael Verardino 1 Romeiro Fernando G 1 Okoshi Katashi 1 Universidade Estadual Paulista Faculdade de Medicina de Botucatu Departamento de Clínica Médica São Paulo SP Brazil Departamento de Clínica Médica - Faculdade de Medicina de Botucatu - Universidade Estadual Paulista - UNESP, São Paulo, SP - Brazil Universidade Estadual Paulista Mailing Address: Marina Politi Okoshi, Faculdade de Medicina de Botucatu, UNESP. Departamento de Clínica Médica. Rubião Júnior, S/N. Postal Code 18618-000, Botucatu, SP - Brasil. E-mail: mpoliti@fmb.unesp.br

Author contributions

Conception and design of the research: Okoshi MP, Capalbo RV, Romeiro FG, Okoshi K; Acquisition of data: Capalbo RV, Okoshi K; Analysis and interpretation of the data: Okoshi MP, Capalbo RV; Obtaining financing and Critical revision of the manuscript for intellectual content: Okoshi MP, Okoshi K; Writing of the manuscript: Okoshi MP, Capalbo RV, Romeiro FG.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 27 10 2016 01 2017 108 1 74 80 05 02 2016 13 05 2016 23 05 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 CNPq 306857/2012-0 306845/2012-1 479085/2013-7 FAPESP 2012/50512-5 2014/21972-3 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

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. Mozaffarian D Benjamin EJ Go AS Arnett DK Blaha MJ Cushman M 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 4 447 454 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. Bocchi EA Marcondes-Braga FG Bacal F Ferraz AS Albuquerque D Rodrigues D 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. Mann DL Pathophysiology of heart failure Bonow RO Mann DL Zipes DP Libby P Braunwald E Braunwald's heart disease Philadelphia Elsevier Saunders 2012 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. Rossignol P Masson S Barlera S Girerd N Castelnovo A Zannad F 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 4 424 433 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. Evans WJ Morley JE Argiles J Bales C Baracos V Guttridge D Cachexia: a new definition Clin Nutr 2008 27 6 793 799 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. Anker SD Negassa A Coats AJ Afzal R Poole-Wilson PA Cohn JN 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 1083 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. Christensen HM Kistorp C Schou M Keller N Zerahn B Frystyk J Prevalence of cachexia in chronic heart failure and characteristics of body composition and metabolic status Endocrine 2013 43 3 626 634 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. Trullas JC Formiga F Montero M Carrera-Izquierdo M Grau-Amorós J Chivite-Guillén D RICA Investigators Impact of weight loss on mortality in chronic heart failure: findings from the RICA Registry Int J Cardiol 2013 168 1 306 311 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. Martins T Vitorino R Amado F Duarte JA Ferreira R Biomarkers for cardiac cachexia: reality or utopia Clin Chim Acta 2014 436 323 328 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. Fulster S Tacke M Sandek A Ebner N Tschope C Doehner W Muscle wasting in patients with chronic heart failure: results from the studies investigating comorbidities aggravating heart failure (SICA-HF) Eur Heart J 2013 34 7 512 519 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. 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. 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 1444 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. 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. 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 2 319 326 15 von Haehling S, Anker SD. Treatment of cachexia: an overview of recent developments. Int J Cardiol. 2015;184:736-42. von Haehling S Anker SD Treatment of cachexia: an overview of recent developments Int J Cardiol 2015 184 736 742 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. 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 4 475 486 17 Okoshi MP, Romeiro FG, Paiva SA, Okoshi K. Heart failure-induced cachexia. Arq Bras Cardiol. 2013;100(5):476-82. Okoshi MP Romeiro FG Paiva SA Okoshi K Heart failure-induced cachexia Arq Bras Cardiol 2013 100 5 476 482 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. Martinez PF Okoshi K Zornoff LA Carvalho RF Oliveira SA Junior Lima AR Chronic heart failure-induced skeletal muscle atrophy, necrosis, and myogenic regulatory factors changes Med Sci Monit 2010 16 12 BR374 BR383 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. Martinez PF Bonomo C Guizoni DM Junior SA Damatto RL Cezar MD Influence of N-acetylcysteine on oxidative stress in slow-twitch soleus muscle of heart failure rats Cell Physiol Biochem 2015 35 1 148 159 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. Lima AR Martinez PF Okoshi K Guizoni DM Zornoff LA Campos DH 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. Lima AR Martinez PF Damatto RL Cezar MD Guizoni DM Bonomo C Heart failure-induced diaphragm myopathy Cell Physiol Biochem 2014 34 2 333 345 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. Damatto RL Martinez PF Lima AR Cezar MD Campos DH Oliveira SA 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. Mancini DM Walter G Reichek N Lenkinski R McCully KK Mullen JL Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure Circulation 1992 85 4 1364 1373 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. 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 1326 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. Springer J Tschirner A Haghikia A von Haehling S Lal H Grzesiak A Prevention of liver cancer cachexia-induced cardiac wasting and heart failure Eur Heart J 2014 35 14 932 941 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. Sugizaki MM Carvalho RF Aragon FF Padovani CR Okoshi K Okoshi MP Myocardial dysfunction induced by food restriction is related to morphological damage in normotensive middle-aged rats J Biomed Sci 2005 12 4 641 649 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. Okoshi K Matsubara LS Okoshi MP Cicogna AC Fioretto JR Padovani CR Food restriction-induced myocardial dysfunction demonstrated by the combination of in vivo and in vitro studies Nutr Res 2002 22 11 1353 1364 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. 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 7 911 919 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. 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 H1333 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. Sugizaki MM Leopoldo AS Okoshi MP Bruno A Conde SJ Lima-Leopoldo AP Severe food restriction induces myocardial dysfunction related to Serca2 activity Can J Physiol Pharmacol 2009 87 9 666 673 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. Molfino A Papa A Gasperini-Zacco ML Muscaritoli M Amoroso A Cascino A Left ventricular mass correlates with lean body mass in patients with disease-associated wasting J Cachexia Sarcopenia Muscle 2014 5 3 251 252 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. 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 9 754 760 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. 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 4 639 648 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. 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 4 244 248 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. Okoshi K Fioretto JR Okoshi MP Cicogna AC Aragon FF Matsubara LS 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 4 607 613 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. Okoshi MP Okoshi K Matsubara LS Pai-Silva MD Gut AL Padovani CR Myocardial remodeling and dysfunction are induced by chronic food restriction in spontaneously hypertensive rats Nutr Res 2006 26 11 567 572 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. Gut AL Sugizaki MM Okoshi MP Carvalho RF Pai-Silva MD Aragon FF Food restriction impairs myocardial inotropic response to calcium and beta-adrenergic stimulation in spontaneously hypertensive rats Nutr Res 2008 28 10 722 727 38 Romeiro FG, Okoshi K, Zornoff LA, Okoshi MP. Gastrointestinal changes associated to heart failure. Arq Bras Cardiol. 2012;98(3):273-7. Romeiro FG Okoshi K Zornoff LA Okoshi MP Gastrointestinal changes associated to heart failure Arq Bras Cardiol 2012 98 3 273 277 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. 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 4 287 296 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. 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. Aquilani R Opasich C Verri M Boschi F Febo O Pasini E Is nutritional intake adequate in chronic heart failure patients? J Am Coll Cardiol 2003 42 7 1218 1223 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. Heymsfield SB Casper K Congestive heart failure: clinical management by use of continuous nasoenteric feeding Am J Clin Nutr 1989 50 3 539 544 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. Rozentryt P von Haehling S Lainscak M Nowak JU Kalantar-Zadeh K Polonski L 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. 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. Aquilani R Opasich C Gualco A Verri M Testa A Pasini E 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 1135 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. Ebner N Springer J Kalantar-Zadehb K Lainscakc M Doehner W Anker SD 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. 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 27 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. Pineda-Juarez JA Sanchez-Ortiz NA Castillo-Martinez L Orea-Tejeda A Cervantes-Gaytan R Keirns-Davis C 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 47 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. Yancy CW Jessup M Bozkurt B Butler J Casey DE Jr Drazner MH 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 1852 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. Du Bois P Pablo Tortola C Lodka D Kny M Schmidt F Song K Angiotensin II induces skeletal muscle atrophy by activating TFEB-mediated MuRF1 expression Circ Res 2015 117 5 424 436 51 Yoshida T, Delafontaine P. Mechanisms of cachexia in chronic disease states. Am J Med Sci. 2015;350(4):250-6. Yoshida T Delafontaine P Mechanisms of cachexia in chronic disease states Am J Med Sci 2015 350 4 250 256 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. Valentova M von Haehling S Bauditz J Doehner W Ebner N Bekfani T 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 1691 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. Sandek A Swidsinski A Schroedl W Watson A Valentova M Herrmann R 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 1102 54 Azhar G, Wei JY. New approaches to treating cardiac cachexia in the older patient. Curr Cardiovasc Risk Rep. 2013;7(6):480-4. Azhar G Wei JY New approaches to treating cardiac cachexia in the older patient Curr Cardiovasc Risk Rep 2013 7 6 480 484 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. Sandek A Anker SD von Haehling S The gut and intestinal bacteria in chronic heart failure Curr Drug Metab 2009 10 1 22 28 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. 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 14074 57 Tang YD, Katz SD. Anemia in chronic heart failure: prevalence, etiology, clinical correlates, and treatment options. Circulation. 2006;113(20):2454-61. Tang YD Katz SD Anemia in chronic heart failure: prevalence, etiology, clinical correlates, and treatment options Circulation 2006 113 20 2454 2461 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. 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 3 248 262 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. Anker SD Comin Colet J Filippatos G Willenheimer R Dickstein K Drexler H FAIR-HF Trial Investigators Ferric carboxymaltose in patients with heart failure and iron deficiency N Engl J Med 2009 361 25 2436 2448 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. Swedberg K Young JB Anand IS Cheng S Desai AS Diaz R RED-HF Committees RED-HF Investigators Treatment of anemia with darbepoetin alfa in systolic heart failure N Engl J Med 2013 368 13 1210 1219 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. Mann DL McMurray JJ Packer M Swedberg K Borer JS Colucci WS Targeted anticytokine therapy in patients with chronic heart failure results of the Randomized Etanercept Worldwide Evaluation (RENEWAL) Circulation 2004 109 13 1594 1602 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. Shaw SM Shah MK Williams SG Fildes JE Immunological mechanisms of pentoxifylline in chronic heart failure Eur J Heart Fail 2009 11 2 113 118 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. 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 1020 64 El Desoky ES. Drug therapy of heart failure: an immunologic view. Am J Ther. 2011;18(5):416-25. El Desoky ES Drug therapy of heart failure: an immunologic view Am J Ther 2011 18 5 416 425 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. Jankowska EA Biel B Majda J Szklarska A Lopuszanska M Medras M Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival Circulation 2006 114 17 1829 1837 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. Caminiti G Volterrani M Iellamo F Marazzi G Massaro R Miceli M 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 10 919 927 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. Iellamo F Volterrani M Caminiti G Karam R Massaro R Fini M Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study J Am Coll Cardiol 2010 56 16 1310 1316 68 Muller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. Mol Metab. 2015;4(6):437-60. Muller TD Nogueiras R Andermann ML Andrews ZB Anker SD Argente J Ghrelin Mol Metab 2015 4 6 437 460 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. Nagaya N Moriya J Yasumura Y Uematsu M Ono F Shimizu W Effects of Ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure Circulation 2004 110 24 3674 3679 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. Santos DP Okoshi K Moreira VO Seiva FR Almeida FL Padovani CR Growth hormone attenuates skeletal muscle changes in experimental chronic heart failure Growth Horm IGF Res 2010 20 2 149 155 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. Osterziel KJ Strohm O Schuler J Friedrich M Hanlein D Willenbrock R 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 1237 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. 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 1711 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. McMurray JJ Adamopoulos S Anker SD Auricchio A Böhm M Dickstein K 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 8 803 869 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. Flynn KE Pina IL Whellan DJ Lin L Blumenthal JA Ellis SJ Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial JAMA 2009 301 14 1451 1459 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. 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 5 554 559 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. Pagan LU Damatto RL Cezar MD Lima AR Bonomo C Campos DH 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. Gomes MJ Martinez PF Campos DH Pagan LU Bonomo C Lima AR 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 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. Souza RW Piedade WP Soares LC Souza PA Aguiar AF Vechetti-Junior IJ 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. 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 H802 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. 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 3 702 709 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. Caminiti G Volterrani M Marazzi G Cerrito A Massaro R Sposato B 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. Wisloff U Stoylen A Loennechen JP Bruvold M Rognmo O Haram PM Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study Circulation 2007 115 24 3086 3094 Artigo de Revisão Caquexia Cardíaca: Perspectivas para a Prevenção e Tratamento Okoshi Marina Politi 1 Capalbo Rafael Verardino 1 Romeiro Fernando G 1 Okoshi Katashi 1 Departamento de Clínica Médica - Faculdade de Medicina de Botucatu - Universidade Estadual Paulista - UNESP, São Paulo, SP - Brasil Correspondência: Marina Politi Okoshi, Faculdade de Medicina de Botucatu, UNESP. Departamento de Clínica Médica. Rubião Júnior, S/N. CEP 18618-000, Botucatu, SP - Brasil. E-mail: mpoliti@fmb.unesp.br

Contribuição dos autores

Concepção e desenho da pesquisa: Okoshi MP, Capalbo RV, Romeiro FG, Okoshi K; Obtenção de dados: Capalbo RV, Okoshi K; Análise e interpretação dos dados: Okoshi MP, Capalbo RV; Obtenção de financiamento e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Okoshi MP, Okoshi K; Redação do manuscrito: Okoshi MP, Capalbo RV, Romeiro FG.

Potencial conflito de interesse

Declaro não haver conflito de interesses pertinentes.

 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 Introdução

A insuficiência cardíaca (IC) é uma importante questão de saúde pública, devido à sua elevada prevalência, gravidade das manifestações clínicas e prognóstico reservado. Dados estatísticos dos Estados Unidos estimam que 5,7 milhões de americanos com mais de 20 anos de idade tem IC; espera-se um aumento de aproximadamente 46% entre 2012 e 2030, resultando em mais de 8 milhões de adultos com IC.1

A IC é causada por anormalidades estruturais e funcionais do coração, levando a deficiências da ejeção ventricular e/ou da capacidade de enchimento ventricular. No Brasil, as principais causas de IC são a isquemia do miocárdio, hipertensão arterial sistêmica, cardiomiopatia dilatada e doença de Chagas, bem como doença valvular.2 Após lesão cardíaca, as consequentes alterações ventriculares moleculares, estruturais e funcionais são conhecidas como remodelação cardíaca. Esse processo é acompanhado pela ativação inflamatória e neuro-hormonal cardíaca e sistêmica, que afeta de maneira adversa o coração em um ciclo vicioso e compromete diferentes órgãos e sistemas.3 Nas últimas décadas, tornou-se claro que as mudanças patológicas envolvem não apenas o sistema cardiovascular, mas também os sistemas renal, neuroendocrinológico, imunológico, hematológico, gastrointestinal, e musculoesquelético, bem como o estado nutricional. Atualmente, estudos experimentais e clínicos têm se concentrado na fisiopatologia das complicações sistêmicas relacionadas à IC, a fim de estabelecer tratamentos para melhorar a qualidade de vida e aumentar a sobrevida.

A caquexia é uma condição patológica prevalente e importante associada com a IC crônica. Sua ocorrência prediz a redução da sobrevida, independente de variáveis relevantes, tais como idade, classe funcional da IC, fração de ejeção e capacidade física.4 Avaliamos estudos sobre caquexia induzida pela IC e discutimos diferentes terapias para sua prevenção e tratamento.

 Definição de caquexia cardíaca

A caquexia tem sido definida como, pelo menos, 5% de perda de peso corporal livre de edema nos 12 meses anteriores (ou um índice de massa corporal < 20 kg / m2) em pacientes com doença crônica e, pelo menos, três dos seguintes critérios clínicos e laboratoriais: diminuição da força muscular, fadiga, anorexia, baixo índice de massa livre de gordura e bioquímica anormal, caracterizada por aumento dos marcadores inflamatórios [proteína C-reativa, interleucina (IL)-6], anemia (Hb < 12 g/dL), ou baixos níveis de albumina sérica (< 3,2 g/dL).5 Como a IC é uma doença inflamatória, Anker et al.6 propuseram que a caquexia cardíaca deveria ser diagnosticada quando a perda de peso corporal é > 6% independente de outros critérios e na ausência de outras doenças graves. Mais recentemente, os investigadores utilizaram um ponto de corte de perda de peso corporal > 5% para caracterizar a caquexia cardíaca.7,8 Deve-se salientar que a caquexia é diferente da desnutrição ou anorexia, que podem ser facilmente revertidas com nutrição adequada.5

Atualmente, diversos biomarcadores têm sido estudados para ajudar a diagnosticar a caquexia cardíaca.9 A perda de massa muscular é um importante componente da caquexia. Ela muitas vezes precede o desenvolvimento da caquexia e pode também prever um prognóstico reservado na IC.10 Diferentemente da caquexia, o diagnóstico de perda de massa muscular depende da avaliação laboratorial de massa muscular, como a absorciometria de raios-x de dupla energia (DEXA), tomografia computadorizada e ressonância magnética.11 A perda muscular também pode ser sugerida pelo mau desempenho durante a ergoespirometria, teste de caminhada de 6 minutos, velocidade da marcha, ou força de preensão manual.11

A importância da caquexia no prognóstico da IC tornou-se mais evidente após a descrição da epidemiologia reversa da obesidade nessa condição. Em pessoas saudáveis, o aumento do índice de massa corporal está associado com um risco elevado de desenvolver doenças cardiovasculares. No entanto, o índice de massa corporal correlacionou-se positivamente com a sobrevivência em pacientes com IC.12 Em uma meta-análise de nove estudos observacionais, a mortalidade foi menor nos pacientes com IC com sobrepeso e obesidade.13 Os mecanismos envolvidos em ambos o paradoxo da obesidade e o prognóstico pior induzido por caquexia não são completamente claros.14

A prevalência da caquexia cardíaca varia entre 8 e 42%, de acordo com a definição de caquexia e população do estudo.6,7,15 Anker et al.6 observaram que 34% dos pacientes ambulatoriais com IC tiveram uma perda de peso corporal ≥6% durante 48 meses de seguimento. Mais recentemente, em pacientes ambulatoriais não diabéticos tratados de forma otimizada, uma perda de peso corporal >5% foi observada em 10,5%.7 A etiologia da caquexia associada à IC é multifatorial e os mecanismos fisiopatológicos subjacentes não estão bem estabelecidos.16 Fatores importantes incluem a redução da ingestão de alimentos, anormalidades gastrointestinais, ativação imunológica e neuro-hormonal, e um desequilíbrio entre os processos anabólicos e catabólicos.16,17

Consequências clínicas da caquexia

As consequências clínicas da caquexia dependem tanto da perda de peso como da inflamação sistêmica, que acompanha oo desenvolvimento da caquexia. A perda severa de peso corporal, mesmo na ausência de inflamação sistêmica, está associada a efeitos deletérios na maior parte dos órgãos e sistemas. A perda de tecido de três compartimentos, tecido magro, massa de gordura e ossos, é geralmente encontrado.7 Nos músculos esqueléticos, um desequilíbrio entre a síntese e a degradação proteica leva a alterações moleculares e atrofia muscular, com diminuição da força e comprometimento das atividades diárias.18-23

As consequências cardíacas da caquexia foram estudadas em condições de coração livre de doenças, tais como o câncer e a desnutrição.24-30 Em indivíduos caquéticos, a massa ventricular esquerda correlacionou-se com a massa corporal magra, mostrando que o coração é submetido a consequências semelhantes às do tecido magro durante a caquexia.31 Em experimentos com animais, a caquexia associada ao câncer induziu disfunção cardíaca e alterações moleculares característicos do processo de remodelação patológica com redução da via de sinalização anabólica.24,25 Observamos que severa restrição alimentar induz alterações ultraestruturais, morfológicas e funcionais leves em corações normais de ratos, que são exacerbadas pela sobrecarga hemodinâmica em ratos hipertensos.32-37 Portanto, a ocorrência de caquexia pode aumentar ainda mais as alterações cardíacas e a IC, em um círculo vicioso fatal. A caquexia também pode exacerbar a anemia associada à IC e alterações gastrointestinais.38

Prevenção e tratamento da caquexia

Como a caquexia cardíaca é multifatorial, tem sido difícil desenvolver uma terapia específica para a sua prevenção e tratamento.11 Uma vez que a perda muscular esquelética pode preceder a caquexia, estratégias preventivas têm sido principalmente dirigidas para a preservação da massa muscular.39 Opções diferentes foram descritas, a maior parte avaliada em pequenos estudos clínicos ou cenários experimentais. Esses incluem suporte nutricional, bloqueio neuro-hormonal, redução da translocação bacteriana intestinal, tratamento da anemia e ferrodeficiência, estimulantes de apetite, agentes imunomoduladores, hormônios anabólicos e esquemas de exercícios físicos (Tabela 1).11 Atualmente, a terapia não farmacológica, como o suporte nutricional e exercícios físicos tem sido considerada como a base para a prevenção e tratamento de caquexia.40

Caquexia cardíaca: perspectivas para a prevenção e tratamento
Abordagem não farmacológica
Suporte Nutricional
Exercícios Físicos
Abordagem farmacológica
Tratamento clinicamente útil
Bloqueio neuro-hormonal
Redução da translocação bacteriana intestinal através do controle do edema periférico
Correção da anemia e ferrodeficiência
Apenas uso experimental
Suplementação de aminoácidos essenciais
Suplementação de aminoácidos de cadeia ramificada
Estimulantes de apetite
Agentes imuno-modulatórios (pentoxifilina, talidomida, estatinas, metotrexato, N-acetilcisteína, inibidores da ativação de células T, antagonistas de quimiocina, interleucina-10, antagonistas de receptores de interleucina-1)
Hormônios anabolizantes (testosterona, indutores de liberação de hormônio do crescimento, hormônio do crescimento)
Vários mecanismos: inibidores e antagonistas da miostatina, bortezomib, inibidores da bioatividade de lipopolissacárideos, e bloqueadores de melanocortina.
Suporte Nutricional

Pacientes não-obesos com IC estável, muitas vezes têm ingestão inadequada de alimentos.41 Portanto, o suporte nutricional é recomendado para obter e manter um peso corporal dentro ou um pouco abaixo da faixa normal, sem edema. Atualmente, não há recomendações específicas para a ingestão de proteínas e energia. A ingestão de 35 kcal/kg/dia mostrou-se segura e eficaz no aumento da massa magra em pacientes com IC.42 Alguns autores recomendaram uma ingestão calórica de pelo menos 31,8 kcal/kg/dia.41 O suporte nutricional deve ser iniciado com pequenas quantidades e aumentado lentamente até o peso corporal desejado ser atingido. O consumo de energia em excesso aumenta as concentrações plasmáticas de catecolaminas e insulina e causam estresse fisiológico. Um aumento nos níveis de insulina induz a reabsorção renal de água e sódio e pode descompensar a IC. Assim, os pacientes devem ser aconselhados a avaliar o seu peso corporal diariamente e adaptar a terapia diurética. A ingestão de proteína deve seguir as recomendações para pessoas saudáveis ​​e pode ser aumentada em casos de perda de proteínas pela má absorção intestinal ou nefropatia.

No entanto, um pequeno estudo mostrou que o uso de suplementos nutricionais orais altamente calóricos e ricos em proteínas melhorou o peso corporal e reduziu os marcadores inflamatórios.43 A ingestão de sódio depende da classe funcional da IC, sendo mais restrito (0,5 a 2g/dia) em casos graves, quando os pacientes precisam ser educados sobre o conteúdo alimentar de sódio.

O uso crônico e vigoroso de diuréticos pode depletar os níveis de potássio e magnésio. Com o aumento da ingestão de carboidratos e aminoácidos e aumento dos níveis de insulina, há um deslocamento de potássio, magnésio e fósforo dos compartimentos extracelulares para os intracelulares, diminuindo, assim, as concentrações plasmáticas destes eletrólitos, o que pode induzir a arritmias cardíacas e morte súbita.

Não há recomendação específica para micronutrientes em IC. Ingestão reduzida de alimentos e uso crônico de diuréticos pode causar deficiência de vitaminas solúveis em água. A tiamina precisa de atenção especial, pois sua deficiência pode prejudicar a função cardíaca.44 A má absorção intestinal pode reduzir os níveis plasmáticos de vitaminas lipossolúveis A, D, E e K.44 Como a congestão hepática e a ascite causam intolerância à ingestão de alimentos, as refeições devem ser frequentes e pequenas. Deve-se ressaltar que, apesar da importância do suporte nutricional, ainda não foi estabelecido se a ingestão adequada de proteínas e energia pode reverter o estado nutricional na IC crônica.45 Além disso, o aumento da ingestão de alimentos pode compensar um pouco da perda de peso, mas pode alterar a distribuição do tecido para o aumento da massa gorda, especialmente quando a perda muscular está presente.46 Portanto, para preservar ou recuperar a massa muscular, o suporte nutricional deve ser combinado com exercícios físicos.

Pequenos estudos recentes têm sugerido que alterações em componentes específicos da dieta podem ser úteis na caquexia cardíaca. Por exemplo, o uso de suplementos de aminoácidos essenciais melhorou o estado nutricional e metabólico na maioria dos pacientes com IC e perda muscular.45 A suplementação com amino ácidos de cadeia ramificada, os quais consistem em leucina, isoleucina e valina, preservou o peso corporal, massa muscular esquelética e função cardíaca em ratos;47 no entanto, não conseguiu beneficiar pacientes com IC.48

Bloqueio da ativação neuro-hormonal

A IC crônica é caracterizada pela ativação cardíaca e sistêmica sustentada do sistema renina-angiotensina-aldosterona e sistemas nervosos adrenérgicos que, em longo prazo, prejudicam a remodelação ventricular. Portanto, o bloqueio desses sistemas é recomendado para todos os pacientes com IC e fração de ejeção reduzida.2,49 O controle de IC com bloqueio neuro-hormonal pode reverter a caquexia independentemente do suporte nutricional.

No entanto, a ativação neuro-hormonal também está diretamente envolvida na atrofia do músculo esquelético. Os efeitos da angiotensina II podem ser evitados pelos inibidores da enzima conversora da angiotensina (iECA) e pelos bloqueadores do receptor da angiotensina 1. Mais recentemente, foi demonstrado que a angiotensina II tem um papel na caquexia e na perda do músculo esquelético através de diferentes mecanismos, tais como o aumento do estresse oxidativo e degradação de proteínas; equilíbrio energético prejudicado; redução do apetite através de alteração nos neuropeptídios orexígenos/anorexígenos no hipotálamo; e inibição da função das células satélite e regeneração muscular.50,51 A administração do inibidor da ECA enalapril diminuiu o risco de perda de peso em pacientes com IC.6 Pode-se argumentar que, como o antagonista da angiotensina II melhora a remodelação cardíaca e função ventricular, também reduziria o risco de desenvolvimento da caquexia. Assim, o bloqueio neuro-hormonal também foi avaliado em caquexia associada ao câncer. Em ratos portadores de tumores, antagonistas da angiotensina e aldosterona, bem como o bloqueio do sistema nervoso adrenérgico atenuaram a perda de peso corporal e de massa magra.25 Em um ensaio clínico de fase III, o inibidor de ECA imidapril preveniu a perda de peso em pacientes com caquexia causada por câncer de pulmão de células não-pequenas e câncer colorretal, mas não por câncer de pâncreas. Quando os dados foram combinados, no entanto, a prevenção da perda de peso não alcançou significância estatística.51 Futuros estudos são necessários para elucidar o papel do bloqueio neuro-hormonal em diferentes causas de caquexia.

 Redução da translocação bacteriana intestinal

Pacientes com IC e edema periférico apresentam aumento da espessura da parede do intestino, o que sugere edema da parede intestinal.38 Entre os parâmetros ecocardiográficos, a combinação de disfunção ventricular direita e elevação da pressão atrial direita fornece a melhor distinção entre pacientes caquéticos e não caquéticos 52. Além disso, a caquexia cardíaca foi associada à congestão intestinal, independentemente do estágio da IC e função cardíaca.52 Os pacientes com IC também têm redução do fluxo sanguíneo intestinal e aumento do crescimento bacteriano justa-mucoso.53 Essas anomalias levam à translocação bacteriana intestinal e ativação do sistema imune.53,54

Endotoxinas bacterianas, também conhecidas como lipopolissacarideos, são potentes indutores de substâncias pró-inflamatórias, tais como o fator de necrose tumoral (TNF)-α. Como a terapia diurética intensiva normalizou o aumento dos níveis de endotoxinas em pacientes com IC com edema periférico,54 os pacientes devem ter o mínimo de edema possível, usando um ou uma combinação de diuréticos.49 Apesar de estudos experimentais que mostram que a antibioticoterapia diminui a translocação bacteriana intestinal, não está provado se a modulação da microflora é segura ou útil na redução da ativação do sistema imune na IC. Portanto, essa abordagem não é recomendada.55

Tratamento da anemia e ferrodeficiência

A prevalência de anemia na IC varia de 4% a 55%, de acordo com a população do estudo e definição da anemia.56 A anemia está associada ao aumento da mortalidade, hospitalização e diminuição da qualidade de vida.57 A etiologia da anemia na IC é multifatorial. A ferrodeficiência está presente em aproximadamente metade dos pacientes com IC, independente da presença de anemia.56 Ambas a anemia e a ferrodeficiência estão associadas com a redução da tolerância ao exercício.58 Como a diminuição da capacidade de exercício está relacionada com redução da massa do músculo esquelético, a anemia e a ferrodeficiência podem estar envolvidas no desenvolvimento da caquexia. A avaliação diagnóstica das causas reversíveis da anemia e seu posterior tratamento são apropriados em todos os pacientes. Atualmente, várias associações médicas sugerem que a ferrodeficiência deve ser rotineiramente avaliada em todos os pacientes com IC e corrigida, se presente.56 Preparações de ferro por via intravenosa são seguras e eficazes no tratamento da ferrodeficiência;58 há pouca informação disponível sobre a eficácia da administração oral de ferro.56 O uso do ferro na correção intravenosa da ferrodeficiência foi associada com a melhora do estado funcional.59 Como o agente estimulador da eritropoiese, darbepoetina alfa, não conseguiu melhorar os resultados clínicos em pacientes com IC com anemia leve a moderada,60 essa classe de fármaco não é recomendada para o tratamento de anemia associada à IC.

 Perspectivas para o tratamento futuro da caquexia

Vários agentes farmacológicos foram testados em cenários experimentais e clínicos para prevenir e tratar a caquexia cardíaca. No entanto, eles atualmente representam perspectivas futuras e não são recomendados para uso clínico.

A perda de apetite é um achado comum em caquexia cardíaca e sua origem é multifatorial.15 Embora estimulantes de apetite como o acetato de megestrol tenham sido usados em outras condições de caquexia, eles não são aprovados para a caquexia cardíaca.

Como dito anteriormente, a IC crônica é seguida pela ativação imunológica, a qual desempenha um papel importante no desenvolvimento da caquexia. Portanto, vários agentes imunomoduladores foram testados na IC. Os antagonistas do fator de necrose tumoral (TNF)-α etanercept e infliximab foram testados em grandes ensaios clínicos com resultados negativos ou neutros.61 A pentoxifilina e a talidomida, também consideradas agentes imunomoduladores, foram usadas em pequenos ensaios com resultados neutros ou favoráveis.62,63 Outros medicamentos imunomoduladores, tais como estatinas, metotrexato, N-acetilcisteína, inibidores de ativação de células T, os antagonistas de quimiocinas, IL-10, e antagonistas dos receptores da IL-1 foram testados em estudos experimentais.19,64

Hormônios anabólicos também foram avaliados na preservação e/ou aumento da massa muscular. Os níveis de testosterona diminuem com a idade; este fenômeno ocorre mais rápido em homens com IC do que em seus pares masculinos saudáveis.65 Baixas concentrações de testosterona foram relacionadas ao aumento do risco de morte, independente da função do ventrículo esquerdo ou a capacidade funcional.39,65 No músculo esquelético, a testosterona aumenta a síntese de proteínas, reduz a degradação de proteínas, e estimula a proliferação e diferenciação de células satélites, aumentando, assim, a massa muscular e a força e melhorando a capacidade de exercício.39 Portanto, a deficiência de androgênios pode estar envolvida no desequilíbrio entre processos anabólicos e catabólicos e contribuir para a perda de massa muscular induzida pela IC e caquexia.65 A suplementação com testosterona foi avaliada em pequenos estudos duplo-cego randomizados, incluindo homens66 e mulheres67 idosos com IC. Como a testosterona melhorou a capacidade funcional e a força muscular, foi considerada a hipótese de que seu uso poderia ser seguro e útil para a IC e a caquexia cardíaca.

A grelina, indutor da liberação do hormônio de crescimento, aumenta a adiposidade e ingestão de alimentos através da modulação de circuitos neurais que controlam a ingestão alimentar, o gasto energético, e o centro de recompensa.68 A grelina foi avaliada em pequenos ensaios em diferentes condições de caquexia.15 Na IC, a administração continuada de grelina melhorou a capacidade de exercício e perda de massa muscular, o que sugere que a grelina e o agonista de seu receptor anamorelina podem ser uma abordagem atraente para futuras investigações.68,69 O hormônio de crescimento (GH) também tem o potencial de melhorar a massa muscular e a capacidade funcional.70 Entretanto, como seus efeitos ainda não foram completamente estabelecidos em pacientes com IC,71,72 estudos adicionais são necessários para esclarecer o papel do GH na IC e caquexia.

Atualmente, vários fármacos tais como inibidores e antagonistas de miostatina, bortezomide (um inibidor da via da ubiquitina-proteassoma), inibidores de bioatividade de lipopolissacarídeos, e bloqueadores de melanocortina têm sido investigados com o propósito de preservar e / ou aumentar a massa muscular em caquexia cardíaca.9,20,22

Exercícios Físicos

Os exercícios físicos são a opção mais promissora para o tratamento da perda de massa muscular em várias doenças. As diretrizes atuais de IC recomendam fortemente a prática regular de exercícios físicos para pacientes estáveis a fim de prevenir e/ou atenuar a remodelação cardíaca e alterações no músculo esquelético.2,49,73 Estudos clínicos e experimentais têm demonstrado que o exercício aeróbico melhora a remodelação cardíaca e função ventricular, bem como aumenta a capacidade funcional e a qualidade de vida.74-76 No músculo esquelético, o treinamento físico reduz o estresse oxidativo, a ativação do sistema ubiquitina-proteassoma, a expressão da miostatina e citocinas pró-inflamatórias, atividade nervosa simpática e a vasoconstrição periférica, restabelece a expressão de proteínas envolvidas no trânsito intracelular de cálcio, e impede a rarefação de capilares e a atrofia de fibras musculares.77-79

Outras modalidades de exercício também têm demonstrado resultados promissores em IC. Por exemplo, um programa de exercícios de resistência melhorou a capacidade funcional48 e uma combinação de hidroterapia com treinamento de resistência melhorou a tolerância ao exercício e perfil hemodinâmico de pacientes com IC.81 Além disso, exercícios aeróbicos de alta intensidade foram seguros e superiores ao treinamento aeróbico de intensidade moderada no aumento do consumo máximo de oxigênio.82 Portanto, estudos adicionais são necessários para estabelecer o melhor protocolo de treinamento em relação ao tipo de exercício, intensidade, duração e frequência para melhorar os resultados na caquexia cardíaca.

 Conclusão

A caquexia desempenha um papel importante na morbidade e mortalidade em pacientes com IC. A compreensão dos mecanismos fisiopatológicos que causam caquexia é um passo essencial para o desenvolvimento de estratégias farmacológicas e não-farmacológicas destinadas a prevenir e tratar a caquexia induzida por IC antes que uma significativa perda de peso corporal e de massa muscular ocorra. Atualmente, a terapia não-farmacológica, tal como suporte nutricional e exercícios físicos, são a base para a prevenção e tratamento da caquexia.

Fontes de financiamento

O presente estudo foi financiado pela FAPESP e CNPq.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

 Agradecimento

Agradecemos à Colin Edward Knaggs pela edição da versão em Inglês.

Apoio financeiro foi fornecido pelo CNPq (306857/2012-0, 306845/2012-1, e 479085/2013-7), FAPESP (2012/50512-5, 2014/21972-3), CAPES, e PROPe, UNESP.