International Journal of Cardiology 162 (2013) 77–85

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International Journal of Cardiology

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Review

Metabolism and the heart: An overview of muscle, fat, and bone metabolism inheart failure

Goran Loncar a,⁎, Susann Fülster b, Stephan von Haehling b,c, Vera Popovic d

a Cardiology Department, Clinical Medical Center Zvezdara, Belgrade, Serbiab Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germanyc Center for Cardiovascular Research (CCR), Charité Medical School, Campus Mitte, Berlin, Germanyd Institute of Endocrinology, Belgrade Medical School, University Clinical Center of Serbia

Abbreviations: BMI, body mass index; BMD, bone macids; GH, growth hormone; HF, heart failure; IGF-1,RANKL, receptor activator of nuclear factor kB ligand.⁎ Corresponding author at: Cardiology Department, Cl

Dimitrija Tucovica 161, 11 000 Belgrade, Serbia.E-mail address: loncar_goran@yahoo.com (G. Loncar

0167-5273/$ – see front matter © 2011 Elsevier Irelanddoi:10.1016/j.ijcard.2011.09.079

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 8 March 2011Received in revised form 14 September 2011Accepted 17 September 2011Available online 7 October 2011

Keywords:BoneFatSkeletal muscleCross-talkHeart failure

Purpose of review: To review original research studies and reviews that present data on changes of body com-partments and its mutual cross-talk with respect to the failing heart predominantly in non-cachectic patientswith chronic heart failure (HF).Recent findings: Thanks to the integrative approach considering the whole organism, several recent studiessuggested a complex network of communication between body compartments in respect to failing heart dur-ing the natural course of body wasting in non-cachectic patients with HF. Interestingly, recent studies suggestthat failing heart trough secretion of natriuretic peptides acts on fat metabolism by inducing adiponectin se-cretion and lipolytic actions. Soluble myostatin released from the failing heart may induce skeletal musclewasting in HF through an endocrine-like mechanism, as well. The likelihood that adipocyte-derived hor-mones influence bone status has been recently proven. Increased serum adiponectin was independently as-sociated with reduced bone mass in elderly patients with non-cachectic HF.

Summary: The concept of body compartments cross-talk in respect to failing heart provides a very interestingparadigm of integrative physiology. Better understanding of body compartments changes and its complexbiochemical interplay may provide more efficacious and forehand treatment to prevent and/or postpone dis-ability and improve quality of life in patients with chronic HF.

© 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Heart failure (HF) is a major public health problem affecting mil-lions of patients worldwide. As the most growing cardiovascularproblem, it occurs in 6–10% of people above 65 years old, and it isthe main cause of morbidity and mortality in this age group [1]. Theoverall prevalence of HF is increasing because of the aging of the pop-ulation, the success in prolonging survival in patients suffering coro-nary events, and the success in postponing coronary events byeffective prevention in those at high risk or those who have alreadysurvived a first event (secondary prevention) [2]. The outcome of pa-tients with HF is gloomy, because 50% of patients are dead at 4 years,and 40% of patients admitted to hospital with HF are dead or read-mitted within 1 year [2,3,4].

ineral density; FFAs, free fattyinsulin like growth factor-1;

inical Medical Center Zvezdara,

).

Ltd. All rights reserved.

HF is a clinical syndrome associated with diverse metabolic distur-bances, many of which may adversely influence musculoskeletal andfat metabolism and provoke weight loss, i.e. exaggerated loss of bodycompartments (bone, skeletal muscle and fat tissue). The phenome-non of involuntary weight loss in chronic disease has been knownfor centuries [5], however, a lot of controversy remains with regardto the definition of cachexia [6]. A consensus meeting leads by inter-national experts in the field recently suggested to diagnose cachexiain cases of weight loss as a consequence of chronic disease, includingHF, exceeding 5% of body weight in conjunction with biochemicalchanges [7]. Such clinical notion is important, because there is astrong association between weight loss and increased mortality inHF patients [8,9]. Substantial weight loss is a strong indicator of im-minent death over the next few months [8]. It is also assumed thatweight loss is not the cause of death but a sensitive marker of poorprognosis. In addition, cachexia in HF, otherwise known as cardiac ca-chexia, is not only associated with poor outcomes, but also with anunfavorable response to drug treatment and poor quality of life [10].As compared to loss of weight, mild obesity (body mass index around30 kg/m2) has been shown to have favorable effects on survival in pa-tients with HF. This phenomenon has been termed the obesity para-dox [11,12], and a vast array of independent publications buttresses

78 G. Loncar et al. / International Journal of Cardiology 162 (2013) 77–85

the view that obese patients with HF fare better in terms of survivalthan patients with normal or low body weight [13,14,15,16]. It isnot clear whether weight gain has the same effect, but it seems thatweight loss should not be pursued in obese HF patients. However, ithas to be admitted that the situation in severe obesity (body massindex N35 kg/m2) may be entirely different, but clear data are lackingfor this situation [11,12].

Cardiac cachexia can cause simultaneous loss of tissue from allthree compartments: lean tissue, fat, and bone [17]. However, thefirst two predominate, particularly during the early stages of weightloss. The factors that trigger the progression from clinically stable,ambulatory HF to cardiac cachexia remain poorly understood andthe timelines differ widely between patients. Additionally, the courseof body composition changes in non-cachectic and stable HF patientsis not clear. While the etiology of weight loss with changes in bodycomposition in HF patients is multifactorial and may involve malnu-trition, neurohormonal and inflammatory activation, catabolic overanabolic dominance, lack of appetite, and malabsorption, the impor-tance of individual pathways and the exact interplay remain un-known [18,19,20]. The increasing morbidity, mortality and disabilityassociated with fractures and loss of muscle mass and strength inHF patients make finding new predictors of osteoporosis and skeletalmuscle loss a priority. Particularly the loss of muscle mass, strengthand function has attracted considerable research interest over thelast years, as these changes can be associated with increased likeli-hood of falls and associated fractures, with increased morbidity lead-ing to frailty, and with low quality of life [21].

Thanks to the integrative approach considering the whole organ-ism, many new findings about the cross-talk between different bodysystems were discovered including the complex interplay betweenbody compartments. For example, based on genetic arguments inmice and humans without HF, the cross-talk between bone remodel-ing and energy metabolism controlled by brain has attracted signifi-cant interest for further research [22]. Thus, a better understandingof the complex crossroads between muscle, fat, and bone metabolismwith respect to the failing heart may provide new insights. This maycontribute to the efforts directed to prevent and postpone the subse-quent disability in these patients and improve their quality of life.

The aim of this review is to summarize data of changes in bodycomposition with the accent on skeletal muscle changes in predomi-nantly stable and non-cachectic HF patients. More specifically, wewanted to analyze the complex cross-talk between body compart-ments with respect to the failing heart with a focus on indirect bio-chemical links. Finally, we suggest potential directions for futureresearch in this area.

2. Changes of body compartments in HF

2.1. Muscle metabolism in HF

Skeletal muscle mass is an important predictor of exercise capaci-ty [23], and it is an independent prognostic indicator of survival in HFpatients [24]. Some degree of muscle wasting is common even in mildheart failure [25]. According to the muscle hypothesis, changes in theskeletal musculature are at the core of the deterioration of patientswith HF [26]. Fatigue and muscle weakness are two of the mainsymptoms experienced by these patients, similar even to sometypes of cancer [27].Wasting of skeletal muscle in HF is marked byquantitative and qualitative changes including biochemical, histolog-ical and functional abnormalities.

Muscle atrophy has been recognized in almost 70% of HF patients,and it occurs even in patients with mild to moderate disease [25]. Aloss of leg muscle mass seems to be an early event in the naturalcourse of non-cachectic chronic HF [17]. In agreement with thisstudy, others demonstrated reduced leg lean mass in non-cachecticHF patients, while there was no difference in arms and trunk lean

mass compared to healthy controls [17, Loncar et al., in preparation].As there is no significant alteration in body composition of the arms,Anker et al. [17] suggested that the progression of HF has initially dif-ferent metabolic and immunological effects in arms and legs. Alongwith the progression of HF to cachectic status, there is further lossof muscle mass in legs and arms [17]. Considering the loss of muscletissue (muscle quantity), it is certainly not surprising that cachecticHF patients show greater muscle weakness than non-cachectic pa-tients (both legs: 39% lower strength), but they also have a 16% re-duction of strength per unit muscle, i.e. impaired muscle quality[28]. A decrease in skeletal muscle mass in HF patients may be associ-ated with a spectrum of consequences including functional limitation,falls and bone fractures, immunodeficiency, impaired thermoregula-tion, and finally frailty or disability. Thus, new knowledge about skel-etal muscle changes in HF may contribute to the efforts directed toprevent and postpone the subsequent disability in these patients. In-deed, recently published data from the Studies InvestigatingCo-morbidities Aggravating Heart Failure (SICA-HF) suggest that18.2% of patients with clinically stable chronic heart failure presentwith muscle loss of more than 2 standard deviations of the mean ap-pendicular muscle mass of a healthy reference population [29], con-sistent with the definition of sarcopenia in elderly adults. Patientswho fulfilled this criterion were older, had lower peak oxygen con-sumption, and lower ejection fraction as compared to patients with-out significant muscle loss [29]. The debate whether muscle wastingin chronic disease should be termed sarcopenia, or whether theterm should be restricted to “healthy aging” remains ongoing [30].

Muscle biopsy studies in HF have consistently demonstratedchanges in muscle histochemistry including a reduced capillary-to-fiber ratio and an increase in type IIX fiber proportions at the expenseof either type I or type IIA muscle fibers [31,32,33]. Several small stud-ies, mostly with a randomized, open-label design, have shown thatsupplementation of essential amino acids may have beneficial effectson these changes andmay improve muscle function [34,35,36]. This isprobably because muscle serves as a protein and energy depot that isused in chronic disease, and replacement of its major componentsmay help restore its normal composition [34,35].Significant musclefiber atrophy has also been reported in HF patients [32]. Ultrastruc-tural morphology of skeletal muscle seems to be further altered bythe presence of an increased number of apoptotic myocytes, whichis strongly related to exercise intolerance in patients with HF [37].

2.1.1. Etiology of skeletal muscle changesThe etiology of muscle loss in patients with HF is complex and

not only multifactorial but includes pathways in which “conse-quences” feedback reinforces “causes”. As an example, it remainsunclear whether physical inactivity in patients with HF, or muscle“disuse”, precedes muscle loss, or whether muscle loss is due tounderlying biological mechanisms, such as oxidative stress, causesreduced physical activity. Although this might plausibly be re-solved through longitudinal studies, it is theoretically likely thatchanges in muscle metabolism is part of a “vicious cycle” that in-volves feedback among several physiological and behavioral sys-tems, making the distinction between “cause” and “consequence”somewhat blurred.

We will only briefly discuss recent data on some of the involvedpatterns in the muscle tissue depletion, because an extensive elab-oration of all would be beyond the scope of this review. Only thefollowing etiological factors will be addressed: ghrelin, the ubiquitin–proteasome system, the nuclear factor-κB (NF-κB) family, and myosta-tin. Somemechanisms are depicted in Fig. 1. These signaling patterns ofmuscle wasting represent recently proposed potential treatmenttargets against body wasting. Previous articles were analyzed in detailfor other etiological factors and mechanisms of muscle wasting in HF[9,10,18,38].

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2.1.2. GhrelinGhrelin is a growth hormone-releasing peptide that was isolat-

ed from the stomach [39]. Serum ghrelin levels were increased incachectic HF patients [40], and its use has recently been proposedas treatment for cachexia [41,42]. Indeed, ghrelin administrationto rats with HF increased body weight, lean and fat mass as wellas food intake [43]. Importantly, intravenous administration ofghrelin improved left ventricular function and exercise capacity,with significant increase of lean body mass and muscle strengthin HF patients [44]. These results suggest that treatment with ghre-lin counteracts muscle wasting in HF patients. Recently, gastricelectrical stimulation has been pursued in order to stimulateghrelin production [45]. Indeed, ghrelin's anti-catabolic actionsmay be mediated, at least in part, by growth hormone-insulin likegrowth factor-1 axis (GH-IGF-1), which is considered essential forskeletal muscle. Nevertheless, ghrelin has been shown to haveGH-independent actions by inhibiting myocyte apoptosis [46] andsympathetic nervous activity [47].

2.1.3. Ubiquitin–proteasome system and NF-κBThe ubiquitin–proteasome system plays a predominant role in the

breakdown of myofibrillar protein and thus in proteolysis of skeletalmuscle (Fig. 1) [48]. Ubiquitin levels are increased in rats with HF,but the system has not been extensively studied in human cardiac ca-chexia [49]. One recent study [50] demonstrated increased protea-some activity in skeletal muscle of patients with chronic HF. In thisstudy, 26 patients with chronic HF and 30 healthy control subjectsunderwent skeletal muscle biopsy from vastus lateralis of the quadri-ceps muscle. Proteasome activity was increased more than 8-fold inHF patients compared to controls (p=0.04), and the highest protea-some activity was observed in the subset of cachectic patients.

The current concept is that the NF-κB transcription family medi-ates the activation of the ubiquitin–proteasome system in most ifnot all muscle catabolic states via upstream signaling molecules thatinclude cytokines or reactive oxygen species [51,52]. Other factorsthat activate the ubiquitin–proteasome system include glucocorticoidhormones and myostatin. Insulin and insulin-like growth factor in-hibit the system [53].

Fig. 1. Mechanisms of pr

2.1.4. MyostatinMyostatin, a member of the transforming growth factor beta

(TGF-β) superfamily, regulates muscle growth and acts as a negativeregulator of skeletal muscle mass [54,55]. In the absence of pathology,myostatin is expressed predominantly in skeletal muscle, althoughsome weak expression is observed in the heart and in adipose tissue[56,57]. In HF, the role of myostatin on skeletal muscle wasting re-mains unclear, however, antibody-directed myostatin inhibition hasbeen shown to improve the mass and function of skeletal musclesin aging mice [58]. Recently, one animal study and two human studiesreported that myostatin was upregulated in cardiac and skeletal mus-cle during HF [59,60,61]. However, a recent study by Zamora et al.[62] failed to report a relevant relationship between myostatin or itspropeptide and parameters of disease severity or prognosis among70 patients with chronic HF. The data with regard to mortality should,however, be viewed with caution, because the number of deaths inthis study remained low. Exercise training in HF exerts beneficial ef-fects on muscle mass and catabolic–anabolic imbalance [63], and inan animal model exercise training was even able to reduce myostatinprotein expression in skeletal muscle and myocardium after 4 weeks[64]. In contrast to these reports, Lima et al. [65] found unchangedmyostatin but reduced follistatin expression in decreased skeletalmuscle trophism. Follistatin is a potent myostatin antagonist [55].Muscle mass was dramatically increased in transgenic mice overex-pressing follistatin [66]. Thus, the results of the present study suggestthat decreased follistatin expression in the skeletal muscle could haveincreased myostatin activity and played a role in the reduced muscletrophism.

2.2. Fat metabolism in HF

The role of fat in patients with HF remains poorly defined. A studyin 27 patients with HF failed to show loss of fat tissue, but showed aloss of lean tissue [67]. Additionally, there was no difference in totalor regional fat mass between non-cachectic HF patients and healthycontrols [17,28]. However, in cachectic patients significant loss of fattissue along with muscle and bone depletion was evident [17]. It istempting to speculate that increased levels of catecholamines andpossibly natriuretic peptides with their lipolytic actions may be

oteolysis in muscle.

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responsible for the loss of adipose tissue that has been observed in ca-chectic HF patients [17]. Tumor necrosis factor-α (TNF-α), which isalso over-expressed in HF [68], plays a major role in fat cell lipolysisas well as in stimulating the ubiquitin–proteasome system [69].

Interestingly, patients affected by major events (urgent hearttransplantations and cardiac death) had a significantly lower percent-age of body fat and total body fat than event-free survivors [70]. In alogistic regression analysis, total fat was a strong and independentpredictor of event-free survival. For every 1% of absolute increase inpercentage of body fat in this population, there was a reduction ofin major clinical events exceeding 13%. The results of this investiga-tion indicate that the improved survival consistently associated withhigher body mass index (BMI) is in fact linked to body fat in patientswith HF. A recent study presented at the 5th Cachexia Conference inBarcelona, which included 498 patients, confirmed that those HF pa-tients with the highest body fat content were least like to die over thecourse of one year: mortality in the quartile with most fat was 3%compared with 14% in the leanest quartile [71]. Thus, it can be sug-gested that high body fat is associated with a more favorable progno-sis in HF, and it is tempting to speculate that fat poses an energydepot to the patient with HF that confers more favorable than detri-mental effects.

One explanation for the positive association between fat mass andsurvival is that patients progressing to higher levels of HF disease se-verity while carrying excess body weight have a greater metabolic re-serve and are more resistant to the increasing catabolic burden[12,72]. Secondly, adipose tissue has been shown to produce TNF-αreceptors, the production of which positively correlates with thelevel of body fat [73]. Therefore, overweight and obese patientswith HF may possess a protective buffer from the negative impact ofincreasing TNF-α by producing higher levels of these receptors com-pared with those who have a normal weight or are underweight. It iswell-known that TNF-α, as a proinflammatory cytokine with catabol-ic effects, is elevated in patients with HF and is also a significant pre-dictor of adverse events [74,75]. Finally, high serum cholesterolcaused by increased fat mass in overweight or obese HF patients,may confer a better survival [76]. Indeed, independent groups ofworkers have shown that higher serum cholesterol values are associ-ated with better survival in patients with HF than lower values[77,78]. The reason for this may be explained by the ability of plasmalipoproteins to bind and neutralize bacterial lipopolysaccharide. Thishypothesis has been called the ‘endotoxin–lipoprotein hypothesis’[79]. A previous article reviews all these issues starting from in-creased endotoxin concentrations entering the bloodstream via thehypoperfused edematous bowel wall and ending with the potentiallyprotective ability of serum lipoproteins in HF [80].

2.3. Bone metabolism in HF

Disorders of bone metabolism, among which osteoporosis is themost prominent, are characteristics of physiological aging [81] andcommonly co-exist with chronic disease (e.g. liver cirrhosis or chronicbronchitis), having adverse influence on quality of life [82]. Bone sta-tus in stable chronic HF patients has been rarely studied so far[83,84,85]. In total, available data suggest that stable pre-transplantchronic HF patients have a significant but only moderately disturbedbone metabolism compared with cachectic HF patients or those whoare candidates for heart transplantation [86]. However, a recent studyfound that reduced bone mineral density (BMD), defined as osteope-nia or osteoporosis, was present in approximately half of elderly pa-tients with stable HF [87]. As expected, patients with severe HF,particularly those with co-existing cachexia, usually demonstrate sig-nificant loss of bone mass [17,88]. Reduced bone mass with subse-quent osteoporosis and higher risk of fractures has also beendescribed in heart transplant recipients, but in this group, accelerated

bone loss is primarily affected by high dose glucocorticoid and cyclo-sporin therapy [89,90].

Apart from the measurement of BMD, additional measurements ofbone turnover can improve the individual risk assessment for boneloss. Bone markers can be used to characterize actual bone metabo-lism and can be helpful to explain possible mechanisms of boneloss. In our recently published study, increased serum levels of osteo-calcin and β-CrossLaps were present in HF patients indicating highbone turnover [83]. Another study showed strong elevation of boneresorption markers in HF patients that correlated negatively withleft ventricular ejection fraction [91]. However, the bone formationmarker (BAP) remained within the normal range. Bone resorptionmarkers in urine were elevated in HF patients, while serum osteocal-cin (marker of bone formation), was normal in HF patients comparedto controls [92]. The authors concluded that accelerated bone loss inHF is caused by increased bone resorption without adequate compen-sation from bone formation.

To date, only one study evaluated changes in bonemass over time inHF patients with the aim to identify its clinical and hormonal determi-nants [84]. This paper provides evidence that men with HF develop ac-celerated bone loss in the course of heart disease. Unexpectedly,reduction in bone mass was accompanied by an increase in fat mass(arms, legs, and total body), and no changes in lean mass during2 year follow-up. Lean mass, measured by dual energy X-ray absorpti-ometry (DEXA), represents very accurately skeletal muscle mass [93].The authors believe that bone tissue is the body compartment inwhich wasting occurs first in HF patients due to its higher sensitivityto anabolic depletion compared to muscle and fat tissue. Prospectivelarge-scale studies, such as the Studies Investigating Co-morbidities Ag-gravating Heart Failure (SICA-HF), a pathophysiological observationalstudy particularly looking at cachexia and obesity prevalence and phe-notype, need to confirm this notion [94].

The importance of low BMD and deteriorated bone metabolismin HF population is that it is likely to increase fracture risk. This iscompounded with poor physical performance, which will increasethe risk of falls. In general, HF is associated with a 4-fold higherrisk of sustaining any fracture requiring hospitalization comparedto patients with other cardiovascular diagnoses apart form HF[95]. In addition, the fracture incidence was 6% within 12 monthsamong stable and non-cachectic HF patients [91]. The most devas-tating complication of osteoporosis is hip fracture, which is associ-ated with high mortality risk and among those who survive, leadsto a loss of function and independence often necessitating admis-sion to long-term care [96].

The findings of the previous studies suggest that lower BMD(osteopenia and osteoporosis) in HF patients is due to multiple fac-tors including vitamin D insufficiency with elevation of parathyroidhormone (PTH), renal dysfunction, increased pro-inflammatory mi-lieu, physical inactivity, hypogonadism, specific drugs, reduced ana-bolic factor IGF-1, all of which negatively affect bone mass and bonehealth. Etiology of bone loss in HF has been extensively presentedand summarized in previous papers [10,18,86].

3. Cross-talk between body compartments with respect tofailing heart

Although different body compartments (fat, muscle, and bone tis-sue) operate independently to a certain degree, each with their owncollection of highly specific cells and regulatory factors, they also de-pend on each other for normal development and function. The cross-talk between body compartments with respect to the failing heartattracts attention of the scientific community in the last years.Research in this domain may provide crucial information on themechanisms of body composition changes, which ultimately lead todisability and poor prognosis in HF (Fig. 2).

Fig. 2. Cross-talk between fat, muscle and bone in respect to failing heart.

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3.1. Cross-talk between failing heart and muscle tissue

3.1.1. Heart and the muscleAn atrophy-inducing factor such as myostatin might be released

directly from the myocardium in HF [54,55]. Indeed, myostatin isupregulated in the heart by pathological insults (such as after infarc-tion injury and volume overload injury), whichmay then significantlycontribute to plasma levels that secondarily affect skeletal musclemass [56,59,97]. The article by Heineke et al. [98] proposed that solu-ble myostatin released from the failing heart induced skeletal musclewasting in HF through an endocrine-like mechanism. Indeed, cardiacstress stimulation in wild-type mice, but not in heart-specific myosta-tin knock-out mice, enhanced circulating myostatin levels. Myostatinprotein expression is also induced in cultured cardiomyocytes in re-sponse to cyclic stretching [99]. Thus, cardiac stress in HF likely in-duces physiologically meaningful myocardial myostatin expressionand release. Myostatin inhibition may be a therapeutic option tocounteract skeletal muscle wasting in HF.

3.1.2. Skeletal muscle and the heartMyostatin is highly and almost exclusively expressed in skeletal

muscle where it strongly inhibits muscle fiber hypertrophy in adult-hood [54,55]. Circulating myostatin levels were elevated in HF pa-tients [60]. Myostatin may also play an active role in cardiacremodeling after injury, given its expression after myocardial infarc-tion and the wide diversity of pathways mediated by TGF-βmembers,such as inflammation, fibrosis, and hypertrophy [56,100,101]. Levelsof the cardiac myostatin pro-peptide (marker of activation) were in-creased in HF and increased after left ventricular assist device supportin patients with dilative cardiomyopathy [60].

3.2. Cross-talk between failing heart and fat tissue

3.2.1. Heart and the fatThe heart and adipose tissue are both endocrine organs, and there

is increasing evidence for cross-talk between them although precise

mechanisms remain poorly defined. Of particular importance is therole that such cross-talk could play in both total body metabolismand cardiac metabolism. Tsukamoto and colleagues add new mecha-nistic insight into the relationship between the failing heart and fatmetabolism supporting the concept of a cross-talk between these sys-tems [102]. The authors demonstrated that natriuretic peptides (atri-al natriuretic peptide [ANP] and B-type natriuretic peptide [BNP]enhance adiponectin production in human adipocytes in vitro andeven in patients with chronic HF via the cGMP pathway. Anothersmall clinical study has previously shown that HF patients who re-ceived ANP infusions had increased plasma levels of serum adiponec-tin levels [103]. How this functionally impacts HF is still unclear,although there is speculation that, in the setting of HF, adiponectinsecretion may occur to attenuate the chronic energy deprivation theheart faces as it switches from predominantly fatty acid oxidation toglucose oxidation [104,105]. In addition, adiponectin secretion couldaid in weight loss, which in the setting of heart failure could be con-sidered a cardiac unloading action. Cachexia in HF was associatedwith an increase in adiponectin levels, irrespective of BMI [106]. Ad-ministration of adiponectin has been shown to decrease body weightin experimental animal models [107] and adiponectin has been sug-gested to increase energy expenditure and induce weight lossthrough a direct effect on the brain [108]. This suggests a role of adi-ponectin in the wasting process in patients with cardiac cachexia.

3.2.2. Fat and the heartAdiponectin could be a link between adipose tissue and the heart,

having an influence on cardiac remodeling [109]. Adiponectin is oneof the most abundant adipose tissue-specific factors and appears toimprove insulin sensitivity and inhibit vascular inflammation [110].Despite the fact that adiponectin is primarily produced by adipose tis-sue, there seems to be an almost paradoxical relationship betweenplasma adiponectin concentrations and BMI. Indeed, it is well estab-lished that in humans plasma adiponectin levels are inversely relatedto BMI and percent body fat [111]. Although mainly secreted by

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adipocytes, adiponectin can also be produced by other tissues and celltypes, including cardiomyocytes.

3.3. Cross-talk between muscle and fat tissue with bone in HF

It is often debated whether fat mass or lean (muscle) mass is amore important determinant of BMD. However, lean mass and themechanical stimuli derived from muscle are often implicated asmajor determinants of bone health and bone loss [112,113].Fogelholm et al. [114] showed that, over a three-year period of weightloss and regain in women, bone mineral density at the radius (a non-weight bearing bone) was more strongly correlated with body weightthan BMD in weight-bearing regions, such as the hip and spine. Thesefindings suggest that body fat may regulate bone metabolism viacirculating, humoral factors whereas the effects of muscle on boneare local andmediated by signaling factors that play a role in mechan-otransduction. Interestingly, elderly men with high lean and low fatmass have the best bone profile [115].

3.3.1. Cross-talk between muscle and bone in HFPrevious studies have shown that in chronic HF, bone and muscle

losses are linked [83,84]. Thus, the association could be explained bydecreased mechanical loading of the muscle on the skeleton becauseof lower physical performance or related bone and muscle loss mayreflect parallel consequences of catabolic over anabolic dominationin HF.

3.3.2. Cross-talk between fat and bone in HF

3.3.2.1. Fat and bone tissue. From epidemiological studies, body weightand BMI are well-described determinants of bone mass [116]. A highBMI is considered protective against developing osteoporosis in bothmen and women, whereas thinness is a major risk factor for sustain-ing osteoporotic fractures [117]. In this view, a higher body weight isbelieved to increase the mechanical stress exerted on the skeletonthrough dynamic loads imposed by muscle and passive loads bywhole body weight, ultimately leading to osteogenesis [118]. In re-cent years, this view on the fat–bone relationship has been chal-lenged by new findings, describing direct and indirect effects ofadipose tissue on bone. Studies on the association of adipose tissuewith bone mass reported inconsistent results regarding the relation-ship of fat and bone mass [119,120], whereas recent publications sug-gested an even negative influence of fat mass on bone after adjustingfor adult body composition [121,122]. The finding of an unfavorableeffect of increasing fat mass on bone, together with significant posi-tive associations with lean mass, formed the well-describedmechanostat theory [121]. The mechanisms underlying inverse rela-tionship between adiposity and bone mass remain incompletely un-derstood. The likelihood that adipocyte-derived hormones influencebone status has been proven [123]. Adiponectin, an adipocyte-derived hormone, has been recently suggested to be involved inbone remodeling [124,125]. Serum adiponectin levels are higher inHF patients compared to healthy controls and are related to deterio-rated prognosis [126,127]. Our recent study provided for the firsttime evidence that increased serum adiponectin was independentlyassociated with reduced BMD in elderly patients with non-cachecticHF [83]. Additionally, a significant positive correlation of serum adi-ponectin and RANKL levels was demonstrated in patients with HF.RANKL is a potent stimulus for bone resorption, and osteoprotegerinhas been shown to prevent RANKL-induced bone loss.

Leptin is also produced by adipocytes and plays an important rolein numerous physiological processes, including bone formation andresorption [128]. Although leptin's effects on bone are complex andoften appear to vary among different study populations and animalmodels, current evidence suggests that leptin signaling in the brainand its relay by the adrenergic system, as well as directly in bone

tissue, plays a major role in mediating the fat-bone axis [128]. In leptin-deficient mice, a high bone mass was observed, which was mediatedthrough a central effect by altering the activity of the sympatheticnervous system, but also a direct effect of leptin on osteoblasts andbone marrow stromal cells has been described [128]. In agreementwith the previous study [121], we have recently showed an inverseand independent relationship between leptin concentrations andbone mineral content in HF patients after controlling for total fat massand renal function [83]. Interestingly, in the multivariate statisticalmodel of the cited study, the influence of fatmass on bonewas strongerthan that of adiponectin and leptin on bone in HF patients, suggestingthat adipose tissue can influence bone through other mechanismsthan by adipokines.

3.3.2.2. Bone and fat tissue. The recents findings confirm that at least inmice, bone is an endocrine organ that acts on energy metabolismthrough a new hormone: osteocalcin [22]. Thus, we can considerthe complex interplay between fat and bone tissue as another exam-ple of a two-way communication. In animal models, osteocalcin actson adipocytes to induce adiponectin secretion, which secondarily re-duce insulin resistance [129]. It is interesting that our recent findingof positive association between adiponectin and osteocalcin in HF pa-tients is in accordance with this revealed cross regulation betweenbone and energy metabolism [83].

3.4. Cross-talk between skeletal muscle and fat in HF

3.4.1. Fat and muscle tissueA recent study demonstrated that ‘adipose-to-muscle interaction’

is a two-way street [130]. It is well-known that muscle disuse leadsto loss of muscle mass as well as an impairment of fat oxidation ca-pacity, which may lead to accumulation of adipose tissue. Thus,according to Sitnick et al. [130] a large adipose tissue mass per se in-fluences the ability of muscle to hypertrophy in response to increasedmechanical load. Free fatty acids (FFAs)modulate the development of in-sulin resistance in skeletal muscle andmight affect adipokine-associatedinsulin resistance as well. Both adiponectin and leptin, as adipocyte-derived hormones, and their receptors are found in skeletal muscle andhave similar acute and chronic effects on muscle metabolism [124,131].Experiments in animals have shown negative influence of leptin onleanmass. After blocking leptin signaling, gain in leanmasswas observedin animals with uremic sarcopenia [132]. We have recently shown thatadiponectin and leptin appeared to be determinants of reduced periph-eral lean compartments and reducedmuscle strength, indicating its pos-sible role in the regulation of peripheral muscle mass and function innon-cachectic patients with HF (Loncar et al., in preparation). Based onour results, one can speculate that adiponectin and leptin may be medi-ators of a systemic inhibitory effect of adipose tissue on peripheralskeletalmuscle in HF by activation of intracellular 5′-AMP-activated pro-tein kinase (AMPK) in skeletal muscle [133]. The recent study of vanBerendoncks et al. [134] provides novel evidence that adiponectin resis-tance occurs in skeletal muscle in CHF. Whether adiponectin expressionin skeletal muscle and circulating levels of adiponectin can be used as abiomarker to evaluate muscle wasting in CHF and especially cardiaccachexia remains to be proven.

3.4.2. Muscle and fat tissueThere is mounting evidence that not only adipose tissue but also

skeletal muscle produces and secretes biologically active proteins or‘myokines’ that facilitate metabolic crosstalk between organ systems.With the discovery that exercise provokes an increase in a number ofcytokines, a possible link between skeletal muscle contractile activitywith metabolic and immune changes was established [135]. In the re-cent review, Pedersen et al. [136] have challenged the generally heldview that interleukin (IL) 6 is a “bad guy” with regard to metabolism.There is strong evidence that an acute increase in circulating levels of

83G. Loncar et al. / International Journal of Cardiology 162 (2013) 77–85

IL-6 enhances fat oxidation, improves insulin-stimulated glucose up-take, and has anti-inflammatory effects. Interestingly, IL-6 is knownto increase lypolysis in adipose tissue [137]. The myokine IL-15 hassolid anabolic effects, and it also seems to play a role in reducing ad-ipose tissue mass. Thus, it is therefore suggested that IL-15 may play arole in muscle-fat crosstalk as well [136,138].

4. Gaps in the literature

Our understanding of the interplay between different body com-partments in HF and particularly between muscle, adipose tissueand bone is far from complete. Some of the major remaining issuesare:

1. Further research is needed to confirm the potential for adiponectinand other adipokines in the cross-talk between musculoskeletalsystem and energy metabolism in HF. Interventional studiesusing the application of adiponectin or its mimicking agent osmo-tin may provide new insight into whether there is a causal rela-tionship between adiponectin and musculoskeletal depletion.

2. Alterations in adipose tissue growth appear to be associated withshifts in the expression of myostatin-signaling genes in both adi-pose and skeletal muscle [57]. To date, there are no data on themyostatin expression in fat tissue in chronic HF. More specifically,it would be of interest to evaluate the potential role of myostatinexpression in the muscle-fat cross-talk which may lead to ‘sarco-penic obesity’ in healthy subjects and patients with HF [139].

3. It would be interesting to assess the potential biochemical cross-talk between skeletal muscle and bone metabolism via myokinesin both healthy subjects and patients with HF.

4. A higher reserve of adipose tissue may have independent protec-tive effects against mortality in patients with HF. The exact physi-ological mechanisms explaining the link between excess fat masswith prognosis in HF are not clear. Thus, new prospective studiesevaluating this issue are needed to definitely clarify the relation-ship between fat mass and prognosis in patients with HF.

5. Both myostatin and ubiquitin–proteasome pathways appear to bevery important in the regulation of muscle atrophy by enhancingproteolysis in the skeletal muscle. This raises the question whetherthere is molecular interplay between the myostatin and protea-some pathways [140]. In favor of the cross-talk between myostatinand proteasome system there are data that increased TNF-α acti-vates both of these pathways in skeletal muscle [59,141].

6. Further studies are warranted to specifically target wasting in pa-tients with heart failure, especially in those with cardiac cachexia.It would be of special interest to evaluate the effect of antagonismof myostatin and ubiquitin–proteasome system on skeletal muscleloss in animal models of HF.

7. The role of myokines may be of importance for beneficial influenceof physical training in healthy subjects [136]. However, there areno data evaluating if beneficial effect of physical training may beregulated by myokines in patients with HF.

5. Conclusion

The integrated functions of different body systems governed bycomplex regulatory mechanisms and coordinated in turn by the auto-nomic nervous system are important considerations in patients withHF. The concept of a cross-talk between body compartments with re-spect to the failing heart provides an interesting paradigm of integra-tive physiology. Better understanding of these mechanisms even innon-cachectic patients may provide more efficacious treatment toprevent and/or postpone disability and improve quality of life inpatients with chronic HF. Despite recent progress in the treatment ofheart failure, an effective treatment strategy for wasting is currentlylacking. However, thanks to the recent clarifications of the mechanisms

of body wasting, new drug classes are emerging in the treatment ofbody wasting, such as myostatin inhibitors, inhibitors of the ubiqui-tin–proteasome pathway, oral ghrelin mimetic, gene therapy andothers. Further studies are warranted to specifically assess these prom-ising classes of drugs targeting body wasting in patients with HF. Theaim of such therapies is to prolong life and to improve quality of life.

The views and ideas proposed in this article may be limited by thefact that only few studies have investigated specifically patients withHF. In many instances, we need to rely on extrapolation from chronicillnesses other than chronic HF. Thus, future research of body com-partments needs to be directed specifically at patients with HF inorder to provide novel therapeutic approaches. In addition, it is tooearly to provide guidance for daily clinical practice that goes beyondthe advice to that weight loss should not be enforced once a diagnosisof heart failure has been reached.

Conflicts of interest

SvH has worked as a consultant for Solartium Dietetics, Berlin,Germany, and for Professional Dietetics, Milan, Italy.

Acknowledgment

Part of this work was funded by the European Commission underthe Seventh Framework Programme 439 (FP7/2007–2013) undergrant agreement number 241558 (SICA-HF). The authors of thismanuscript have certified that they comply with the Principles ofEthical Publishing in the International Journal of Cardiology.

References

[1] Lloyd-Jones DM, Larson MG, Leip EP, et al. Framingham Heart Study. Lifetime riskfor developing congestive heart failure: the Framingham Heart Study. Circulation2002;106:3068–72.

[2] Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive heart failure in the com-munity: trends in incidence and survival in a 10-year period. Arch Intern Med1999;159:29–34.

[3] Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ. More ‘malignant’ thancancer? Five-year survival following a first admission for heart failure. Eur JHeart Fail 2001;3:315–22.

[4] Cowie MR, Wood DA, Coats AJ, et al. Survival of patients with a new diagnosis ofheart failure: a population based study. Heart 2000;83:505–10.

[5] Katz AM, Katz PB. Diseases of the heart in the works of Hippocrates. Br Heart J1962;24:257–64.

[6] Springer J, von Haehling S, Anker SD. The need for a standardized definition forcachexia in chronic illness. Nat Clin Pract Endocrinol Metab 2006;2:416–7.

[7] von Haehling S, Anker SD. Cachexia as a major underestimated and unmetmedical need: facts and numbers. J Cachexia Sarcopenia Muscle 2010;1:1–5.

[8] Pocock SJ, McMurray JJ, Dobson J, et al. Weight loss and mortality risk in patientswith chronic heart failure in the candesartan in heart failure: assessment of re-duction in mortality and morbidity (CHARM) programme. Eur Heart J 2008;29:2641–50.

[9] Anker SD, Negassa A, Coats AJ, et al. Prognostic importance of weight loss inchronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study. Lancet 2003;361:1077–83.

[10] von Haehling S, Lainscak M, Springer J, Anker SD. Cardiac cachexia: a systematicoverview. Pharmacol Ther 2009;121:227–52.

[11] von Haehling S, Doehner W, Anker SD. Revisiting the obesity paradox in heartfailure: new insights? Eur J Heart Fail 2011;13:130–2.

[12] Anker SD, von Haehling S. The obesity paradox in heart failure: accepting realityand making rational decisions. Clin Pharmacol Ther 2011;90:188–90.

[13] Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, Tillisch JH. Therelationship between obesity and mortality in patients with heart failure. J AmColl Cardiol 2001;38:789–95.

[14] Curtis JP, Selter JG, Wang Y, et al. The obesity paradox: body mass index and out-comes in patients with heart failure. Arch Intern Med 2005;165:55–61.

[15] Kenchaiah S, Pocock SJ, Wang D, et al. CHARM Investigators. Body mass indexand prognosis in patients with chronic heart failure: insights from the candesar-tan in heart failure: assessment of reduction in mortality and morbidity(CHARM) program. Circulation 2007;116:627–36.

[16] Clark AL, Knosalla C, Birks E, et al. Heart transplantation in heart failure: theprognostic importance of body mass index at time of surgery and subsequentweight changes. Eur J Heart Fail 2007;9:839–44.

[17] Anker SD, Ponikowski PP, Clark AL, et al. Cytokines and neurohormones relatingto body composition alterations in the wasting syndrome of chronic heart fail-ure. Eur Heart J 1999;20:683–93.

84 G. Loncar et al. / International Journal of Cardiology 162 (2013) 77–85

[18] von Haehling S, Doehner W, Anker SD. Nutrition, metabolism, and the complexpathophysiology of cachexia in chronic heart failure. Cardiovasc Res 2007;73:298–309.

[19] Strassburg S, Springer J, Anker SD. Muscle wasting in cardiac cachexia. Int J Bio-chem Cell Biol 2005;37:1938–47.

[20] Braun TP, Marks DL. Pathophysiology and treatment of inflammatory anorexia inchronic disease. J Cachexia Sarcopenia Muscle 2010;1:135–45.

[21] von Haehling S, Morley JE, Anker SD. An overview of sarcopenia: facts and num-bers on prevalence and clinical impact. J Cachexia Sarcopenia Muscle 2010;1:129–33.

[22] ConfavreuxCB, Levine RL, KarsentyG. A paradigmof integrative physiology, the cross-talk between bone and energy metabolisms. Mol Cell Endocrinol 2009;310:21–9.

[23] Cicoira M, Zanolla L, Franceschini L, et al. Skeletal muscle mass independently pre-dicts peak oxygen consumption and ventilatory response during exercise in nonca-chectic patients with chronic heart failure. J Am Coll Cardiol 2001;37:2080–5.

[24] Anker SD, Ponikowski P, Varney S, et al. Wasting as independent risk factor formortality in chronic heart failure. Lancet 1997;349:1050–3.

[25] Mancini DM, Walter G, Reichek N, et al. Contribution of skeletal muscle atrophyto exercise intolerance and altered muscle metabolism in heart failure. Circula-tion 1992;85:1364–73.

[26] Coats AJ, Clark AL, Piepoli M, Volterrani M, Poole-Wilson PA. Symptoms andquality of life in heart failure: the muscle hypothesis. Br Heart J 1994;72:S36–9.

[27] Kilgour RD, Vigano A, Trutschnigg B, et al. Cancer-related fatigue: the impact ofskeletal muscle mass and strength in patients with advanced cancer. J CachexiaSarcopenia Muscle 2010;1:177–85.

[28] Anker SD, Swan JW, Volterrani M, et al. The influence of muscle mass, strength,fatigability and blood flow on exercise capacity in cachectic and non-cachecticpatients with chronic heart failure. Eur Heart J 1997;18:259–69.

[29] Fuelster S, Kung T, Sandek A, et al. Sarcopenia in patients with chronic heart failure:results from the SICA-HF Study. (Suppl)Eur J Heart Fail 2011;10:S57 (Abstract).

[30] Fearon K, Evans WJ, Anker SD. Myopenia—a new universal term for muscle wast-ing. J Cachexia Sarcopenia Muscle 2011;2:1–3.

[31] Williams AD, Selig S, Hare DL, et al. Reduced exercise tolerance in CHF maybe related to factors other than impaired skeletal muscle oxidative capacity.J Card Fail 2004;10:141–8.

[32] Massie BM, Simonini A, Sahgal P, Wells L, Dudley GA. Relation of systemic andlocal muscle exercise capacity to skeletal muscle characteristics in men withcongestive heart failure. J Am Coll Cardiol 1996;27:140–5.

[33] Schaufelberger M, Eriksson BO, Lönn L, Rundqvist B, Sunnerhagen KS, SwedbergK. Skeletal muscle characteristics, muscle strength and thigh muscle area in pa-tients before and after cardiac transplantation. Eur J Heart Fail 2001;3:59–67.

[34] Aquilani R, Viglio S, Iadarola P, et al. Oral amino acid supplements improve exer-cise capacities in elderly patients with chronic heart failure. Am J Cardiol2008;101:104E–10E.

[35] Macchi A, Franzoni I, Buzzetti F, et al. The role of essential amino acid supple-mentation in chronic heart failure. Eur Heart J 2009;30(Suppl):869 (Abstract).

[36] Dioguardi FS. Clinical use of amino acids as dietary supplement: pros and cons.J Cachex Sarcopenia Muscle 2011;2:75–80.

[37] Duscha BD, Kraus WE, Keteyian SJ, et al. Capillary density of skeletal muscle: a con-tributing mechanism for exercise intolerance in class II–III chronic heart failure in-dependent of other peripheral alterations. J Am Coll Cardiol 1999;33:1956–63.

[38] Miján-de-la-Torre A. Recent insights on chronic heart failure, cachexia and nutri-tion. Curr Opin Clin Nutr Metab Care 2009;12:251–7.

[39] Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is agrowth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–60.

[40] Nagaya N, Uematsu M, Kojima M, et al. Elevated circulating level of ghrelin in ca-chexia associated with chronic heart failure: relationships between ghrelin andanabolic/catabolic factors. Circulation 2001;104:2034–8.

[41] Akamizu T, Kangawa K. Ghrelin for cachexia. J Cachexia Sarcopenia Muscle2010;1:169–76.

[42] Müller TD, Perez-Tilve D, Tong J, Pfluger PT, Tschöp MH. Ghrelin and its potentialin the treatment of eating/wasting disorders and cachexia. J Cachexia SarcopeniaMuscle 2010;1:159–67.

[43] Akashi YJ, Palus S, Datta R, et al. No effects of human ghrelin on cardiac functiondespite profound effects on body composition in a rat model of heart failure. Int JCardiol 2009;137:267–75.

[44] Nagaya N, Moriya J, Yasumura Y, et al. Effects of ghrelin administration on leftventricular function, exercise capacity, and muscle wasting in patients withchronic heart failure. Circulation 2004;110:3674–9.

[45] Gallas S, Gourcerol G, Ducrotté P, Déchelotte P, Leroi AM, Fetissov SO. Gastricelectrical stimulation increases ghrelin production: a new approach to anorexia–cachexia. J Cachexia Sarcopenia Muscle 2010;1:47 (Abstract 055).

[46] Baldanzi G, Filigheddu N, Cutrupi S, et al. Ghrelin and des-acyl ghrelin inhibit celldeath in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002;159:1029–37.

[47] Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M. Central ghrelin modulatessympathetic activity in conscious rabbits. Hypertension 2002;40:694–9.

[48] Mitch WE, Goldberg AL. Mechanisms of muscle wasting. The role of the ubiqui-tin–proteasome pathway. N Engl J Med 1996;335:1897–905.

[49] Libera LD, Vescovo G. Muscle wastage in chronic heart failure, between apopto-sis, catabolism and altered anabolism: a chimaeric view of inflammation? CurrOpin Clin Nutr Metab Care 2004;7:435–41.

[50] Szabó T, Sandek A, Hartmann A, et al. Increased proteasome activity in skeletalmuscle of patients with chronic heart failure-a fluent transition to cachectic dis-ease state? J Cachexia Sarcopenia Muscle 2010;1:45–6 (Abstract 006).

[51] Cai D, Frantz JD, Tawa Jr NE, et al. IKKbeta/NF-kappaB activation causes severemuscle wasting in mice. Cell 2004;119:285–98.

[52] Jackman RW, Kandarian SC. The molecular basis of skeletal muscle atrophy. Am JPhysiol Cell Physiol 2004;287:C834–43.

[53] Ventadour S, Attaix D. Mechanisms of skeletal muscle atrophy. Curr Opin Rheu-matol 2006;18:631–5.

[54] McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice bya new TGF-beta superfamily member. Nature 1997;387:83–90.

[55] Lee SJ. Regulation of muscle mass by myostatin. Annu Rev Cell Dev Biol 2004;20:61–86.

[56] Shyu KG, Lu MJ, Wang BW, Sun HY, Chang H. Myostatin expression in ventricularmyocardium in a rat model of volume-overload heart failure. Eur J Clin Invest2006;36:713–9.

[57] Allen DL, Cleary AS, Speaker KJ, et al. Myostatin, activin receptor IIb, andfollistatin-like-3 gene expression are altered in adipose tissue and skeletal mus-cle of obese mice. Am J Physiol Endocrinol Metab 2008;294:E918–27.

[58] Murphy KT, Koopman R, Leger B, Trieu J, Ibebunjo C, Lynch GS. Novel effects ofmyostatin inhibition on skeletal muscles of aging mice: implications for sarcope-nia. J Cachexia Sarcopenia Muscle 2010;1:70–1 (Abstract 063).

[59] Lenk K, Schur R, Linke A, et al. Impact of exercise training on myostatin expres-sion in the myocardium and skeletal muscle in a chronic heart failure model. EurJ Heart Fail 2009;11:342–8.

[60] George I, Bish LT, Kamalakkannan G, et al. Myostatin activation in patients withadvanced heart failure and after mechanical unloading. Eur J Heart Fail 2010;12:444–53.

[61] Gruson D, Ahn SA, Ketelslegers JM, Rousseau MF. Increased plasma myostatin inheart failure. Eur J Heart Fail 2011;13:734–6.

[62] Zamora E, Simó R, Lupón J, et al. Serum myostatin levels in chronic heart failure.Rev Esp Cardiol 2010;63:992–6.

[63] Lenk K, Schuler G, Adams V. Skeletal muscle wasting in cachexia and sarcopenia:molecular pathophysiology and impact of exercise training. J Cachexia Sarcope-nia Muscle 2010;1:9–21.

[64] Lenk K, Adams V, Linke A, Schur R, Erbs S, Schuler G. Impact of exercise trainingon myostatin expression in the myocardium and skeletal muscle in a chronicheart failure model and patients with chronic heart failure (CHF). J Cachexia Sar-copenia Muscle 2010;1:86 (Abstract 097).

[65] Lima AR, Martinez PF, Okoshi K, et al. Myostatin and follistatin expression inskeletal muscles of rats with chronic heart failure. Int J Exp Pathol 2010;91:54–62.

[66] Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. ProcNatl Acad Sci U S A 2001;98:9306–11.

[67] Thomas RD, Silverton NP, Burkinshaw L, Morgan DB. Potassium depletion andtissue loss in chronic heart-disease. Lancet 1979;2:9–11.

[68] von Haehling S, Jankowska EA, Anker SD. Tumour necrosis factor-alpha and thefailing heart-pathophysiology and therapeutic implications. Basic Res Cardiol2004;99:18–28.

[69] von Haehling S, Genth-Zotz S, Anker SD, Volk HD. Cachexia: a therapeutic ap-proach beyond cytokine antagonism. Int J Cardiol 2002;85:173–83.

[70] Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis inchronic systolic heart failure: the obesity paradox. Am J Cardiol 2003;91:891–4.

[71] von Haehling S, Stepney R, Anker SD. Advances in understanding and treatingcardiac cachexia: highlights from the 5th Cachexia Conference. Int J Cardiol2010;144:347–9.

[72] Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor,paradox, and impact of weight loss. J Am Coll Cardiol 2009;53:1925–32.

[73] Mohamed-Ali V, Goodrick S, Bulmer K, Holly JM, Yudkin JS, Coppack SW. Produc-tion of soluble tumor necrosis factor receptors by human subcutaneous adiposetissue in vivo. Am J Physiol 1999;277:E971–5.

[74] Feldman AM, Combes A, Wagner D, et al. The role of tumor necrosis factor in thepathophysiology of heart failure. J Am Coll Cardiol 2000;35:537–44.

[75] Anker SD, von Haehling S. Inflammatory mediators in chronic heart failure: anoverview. Heart 2004;90:464–70.

[76] von Haehling S, Schefold JC, Springer J, Anker SD. The cholesterol paradox revis-ited: heart failure, systemic inflammation, and beyond. Heart Fail Clin 2008;4:141–51.

[77] Rauchhaus M, Clark AL, Doehner W, et al. The relationship between cholesteroland survival in patients with chronic heart failure. J Am CollCardiol 2003;42:1933–40.

[78] Horwich TB, Hamilton MA, Maclellan WR, Fonarow GC. Low serum totalcholesterol is associated with marked increase in mortality in advancedheart failure. J Card Fail 2002;8:216–24.

[79] Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis. Lancet2000;356:930–3.

[80] Sandek A, Utchill S, Rauchhaus M. The endotoxin-lipoprotein hypothesis: an up-date. Arch Med Sci 2007;3:S81–90.

[81] Orwoll ES, Oviatt SK, McClung MR, Deftos LJ, Sexton G. The rate of bone mineralloss in normal men and the effects of calcium and cholecalciferol supplementa-tion. Ann Intern Med 1990;112:29–34.

[82] Eastell R, Boyle IT, Compston J, et al. Management of male osteoporosis: report ofthe UK Consensus Group. QJM 1998;91:71–92.

[83] Bozic B, Loncar G, Prodanovic N, et al. Relationship between high circulatingadiponectin with bone mineral density and bone metabolism in elderly maleswith chronic heart failure. J Card Fail 2010;16:301–7.

[84] Jankowska EA, Jakubaszko J, Cwynar A, et al. Bone mineral status and bone lossover time in men with chronic systolic heart failure and their clinical and hor-monal determinants. Eur J Heart Fail 2009;11:28–38.

85G. Loncar et al. / International Journal of Cardiology 162 (2013) 77–85

[85] Kenny AM, Boxer R, Walsh S, Hager WD, Raisz LG. Femoral bone mineral densityin patients with heart failure. Osteoporos Int 2006;17:1420–7.

[86] Zittermann A, Schleithoff SS, Koerfer R. Markers of bone metabolism in conges-tive heart failure. Clin Chim Acta 2006;366:27–36.

[87] Abou-Raya S, Abou-Raya A. Osteoporosis and congestive heart failure (CHF) in theelderly patient: double disease burden. Arch Gerontol Geriatr 2009;49:250–4.

[88] Anker SD, Clark AL, Teixeira MM, Hellewell PG, Coats AJ. Loss of bone mineral inpatients with cachexia due to chronic heart failure. Am J Cardiol 1999(b;83:612–5.

[89] Glendenning P, Kent GN, Adler BD, et al. High prevalence of osteoporosis in car-diac transplant recipients and discordance between biochemical turnovermarkers and bone histomorphometry. Clin Endocrinol (Oxf) 1999;50:347–55.

[90] Shane E, Rivas M, Staron RB, et al. Fracture after cardiac transplantation: a pro-spective longitudinal study. J Clin Endocrinol Metab 1996;81:1740–6.

[91] Frost RJ, Sonne C, Wehr U, Stempfle HU. Effects of calcium supplementation onbone loss and fractures in congestive heart failure. Eur J Endocrinol 2007;156:309–14.

[92] Shane E, Mancini D, Aaronson K, et al. Bone mass, vitamin D deficiency, and hy-perparathyroidism in congestive heart failure. Am J Med 1997;103:197–207.

[93] Prior BM, Cureton KJ, Modlesky CM, et al. In vivo validation of whole body com-position estimates from dual-energy X-ray absorptiometry. J Appl Physiol1997;83:623–30.

[94] von Haehling S, Lainscak M, Doehner W, et al. Diabetes mellitus, cachexia andobesity in heart failure: rationale and design of the Studies InvestigatingCo-morbidities Aggravating Heart Failure (SICA-HF). J Cachexia Sarcopenia Mus-cle 2010;1:187–94.

[95] vanDiepen S, Majumdar SR, Bakal JA, McAlister FA, Ezekowitz JA. Heart failure is arisk factor for orthopedic fracture: a population-based analysis of 16,294 patients.Circulation 2008;118:1946–52.

[96] Jiang HX, Majumdar SR, Dick DA, et al. Development and initial validation of arisk score for predicting in-hospital and 1-year mortality in patients with hipfractures. J Bone Miner Res 2005;20:494–500.

[97] Sharma M, Kambadur R, Matthews KG, et al. Myostatin, a transforming growthfactor-beta superfamily member, is expressed in heart muscle and is upregu-lated in cardiomyocytes after infarct. J Cell Physiol 1999;180:1–9.

[98] Heineke J, Auger-Messier M, Xu J, et al. Genetic deletion of myostatin from theheart prevents skeletal muscle atrophy in heart failure. Circulation 2010;121:419–25.

[99] Shyu KG, Ko WH, Yang WS, Wang BW, Kuan P. Insulin-like growth factor-1mediates stretch-induced upregulation of myostatin expression in neonatalrat cardiomyocytes. Cardiovasc Res 2005;68:405–14.

[100] Morissette MR, Cook SA, Foo S, et al. Myostatin regulates cardiomyocyte growththrough modulation of Akt signaling. Circ Res 2006;99:15–24.

[101] Artaza JN, Reisz-Porszasz S, Dow JS, et al. Alterations in myostatin expression areassociated with changes in cardiac left ventricular mass but not ejection fractionin the mouse. J Endocrinol 2007;194:63–76.

[102] Tsukamoto O, Fujita M, Kato M, et al. Natriuretic peptides enhance the produc-tion of adiponectin in human adipocytes and in patients with chronic heart fail-ure. J Am Coll Cardiol 2009;53:2070–7.

[103] Tanaka T, Tsutamoto T, Sakai H, et al. Effect of atrial natriuretic peptide on adipo-nectin in patients with heart failure. Eur J Heart Fail 2008;10:360–6.

[104] McEntegart MB, Awede B, Petrie MC, et al. Increase in serum adiponectin con-centration in patients with heart failure and cachexia: relationship with leptin,other cytokines, and B-type natriuretic peptide. Eur Heart J 2007;28:829–35.

[105] Fujioka D, Kawabata K, Saito Y, et al. Role of adiponectin receptors in endothelin-induced cellular hypertrophy in cultured cardiomyocytes and their expression ininfarcted heart. Am J Physiol Heart Circ Physiol 2006;290:H2409–16.

[106] Araújo JP, Lourenço P, Rocha-Gonçalves F, Ferreira A, Bettencourt P. Adiponectinis increased in cardiac cachexia irrespective of body mass index. Eur J Heart Fail2009;11:567–72.

[107] Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30-kDa adi-pocyte complement-related protein increases fatty acid oxidation in muscleand causes weight loss in mice. Proc Natl Acad Sci U S A 2001;98:2005–10.

[108] Qi Y, Takahashi N, Hileman SM, et al. Adiponectin acts in the brain to decreasebody weight. Nat Med 2004;10:524–9.

[109] Ybarra J, Resmini E, Planas F, et al. Relationship between adiponectin and leftatrium size in uncomplicated obese patients: adiponectin, a link between fatand heart. Obes Surg 2009;19:1324–32.

[110] Lyon CJ, Law RE, Hsueh WA. Mini review: adiposity, inflammation, and athero-genesis. Endocrinology 2003;144:2195–200.

[111] Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific pro-tein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79–83.

[112] Eisman JA. Good, good, good… good vibrations: the best option for better bones?Lancet 2001;358:1924–5.

[113] Qin YX, Lam H, Ferreri S, Rubin C. Dynamic skeletal muscle stimulation and itspotential in bone adaptation. J Musculoskelet Neuronal Interact 2010;10:12–24.

[114] Fogelholm GM, Sievänen HT, Kukkonen-Harjula TK, Pasanen ME. Bone mineraldensity during reduction, maintenance and regain of body weight in premeno-pausal, obese women. Osteoporos Int 2001;12:199–206.

[115] Benetos A, Zervoudaki A, Kearney-Schwartz A, et al. Effects of lean and fat masson bone mineral density and arterial stiffness in elderly men. Osteoporos Int2009;20:1385–91.

[116] Hannan MT, Felson DT, Anderson JJ. Bone mineral density in elderly men andwomen: results from the Framingham osteoporosis study. J Bone Miner Res1992;7:547–53.

[117] De Laet C, Kanis JA, Odén A, et al. Body mass index as a predictor of fracture risk:a meta-analysis. Osteoporos Int 2005;16:1330–8.

[118] Beck TJ, Oreskovic TL, Stone KL, et al. Structural adaptation to changing skeletalload in the progression toward hip fragility: the study of osteoporotic fractures.J Bone Miner Res 2001;16:1108–19.

[119] Yamauchi M, Sugimoto T, Yamaguchi T, et al. Plasma leptin concentrations areassociated with bone mineral density and the presence of vertebral fracturesin postmenopausal women. Clin Endocrinol (Oxf) 2001;55:341–7.

[120] Goulding A, Taylor RW. Plasma leptin values in relation to bone mass and densi-ty and to dynamic biochemical markers of bone resorption and formation inpostmenopausal women. Calcif Tissue Int 1998;63:456–8.

[121] Taes YE, Lapauw B, Vanbillemont G, et al. Fat mass is negatively associated withcortical bone size in young healthy male siblings. J Clin Endocrinol Metab2009;94:2325–31.

[122] Travison TG, Araujo AB, Esche GR, Beck TJ, McKinlay JB. Lean mass and not fatmass is associated with male proximal femur strength. J Bone Miner Res2008;23:189–98.

[123] Reid IR. Relationships among body mass, its components, and bone. Bone2002;31:547–55.

[124] Luo XH, Guo LJ, Yuan LQ, et al. Adiponectin stimulates human osteoblasts prolif-eration and differentiation via the MAPK signaling pathway. Exp Cell Res2005;309:99–109.

[125] Luo XH, Guo LJ, Xie H, et al. Adiponectin stimulates RANKL and inhibits OPG ex-pression in human osteoblasts through the MAPK signaling pathway. J BoneMiner Res 2006;21:1648–56.

[126] Tamura T, Furukawa Y, Taniguchi R, et al. Serum adiponectin level as an inde-pendent predictor of mortality in patients with congestive heart failure. Circ J2007;71:623–30.

[127] George J, Patal S, Wexler D, et al. Circulating adiponectin concentrations inpatients with congestive heart failure. Heart 2006;92:1420–4.

[128] Hamrick MW, Ferrari SL. Leptin and the sympathetic connection of fat to bone.Osteoporos Int 2008;19:905–12.

[129] Lee NK, Sowa H, Hinoi E, et al. Endocrine regulation of energy metabolism by theskeleton. Cell 2007;130:456–69.

[130] Sitnick M, Bodine SC, Rutledge JC. Chronic high fat feeding attenuatesload-induced hypertrophy in mice. J Physiol 2009;587:5753–65.

[131] Khosla S, Atkinson EJ, Riggs BL, Melton LJ. Relationship between body composi-tion and bone mass in women. J Bone Miner Res 1996;11:857–63.

[132] Roberts TK, Bailey JL. Beyond nutrition: neuropeptide signaling and muscle massmaintenance in chronic kidney disease. Kidney Int 2008;74:143–5.

[133] Lafontan M, Viguerie N. Role of adipokines in the control of energy metabolism:focus on adiponectin. Curr Opin Pharmacol 2006;6:580–5.

[134] Van Berendoncks AM, Garnier A, Beckers P, et al. Exercise training reverses adi-ponectin resistance in skeletal muscle of patients with chronic heart failure.Heart 2011;97:1403–9.

[135] Carey AL, Febbraio MA. Interleukin-6 and insulin sensitivity: friend or foe?Diabetologia 2004;47:1135–42.

[136] Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008;88:1379–406.

[137] Pedersen BK, Fischer CP. Beneficial health effects of exercise-the role of IL-6 as amyokine. Trends Pharmacol Sci 2007;28:152–6.

[138] Quinn LS, Strait-Bodey L, Anderson BG, Argilés JM, Havel PJ. Interleukin-15 stim-ulates adiponectin secretion by 3 T3-L1 adipocytes: evidence for a skeletalmuscle-to-fat signaling pathway. Cell Biol Int 2005;29:449–57.

[139] Pathy MS, Sinclair AJ, Morley JE. Principles and practice of geriatric medicine. 4thEdition. John Wiley & Sons, Ltd; 2006. p. 920–1.

[140] Springer J, Adams V, Anker SD. Myostatin: regulator of muscle wasting in heartfailure and treatment target for cardiac cachexia. Circulation 2010;121:354–6.

[141] Adams V, Linke A, Wisloff U, et al. Myocardial expression of Murf-1 and MAFbxafter induction of chronic heart failure: effect on myocardial contractility. Cardi-ovasc Res 2007;73:120–9.