CHF MAY/JUNE 2003148 SKELETAL MUSCLE AND HEART FAILURE

Recent studies suggest that changes in the periphery, likethose occurring in the skeletal muscles of patients withchronic heart failure, might play an important role inthe origin of symptoms and exercise intolerance in thiscondition. Biochemical and histologic changes in theskeletal muscles of chronic heart failure patients relatewith the degree of exercise intolerance better than hemo-dynamics parameters. A reduction in skeletal musclemass represents another important determinant of exer-cise intolerance in chronic heart failure patients. The re-lationship between skeletal muscle changes and exerciseintolerance suggests the possibility of modifying the pe-ripheral changes in order to improve functional capacityin chronic heart failure patients. Recent studies haveshown that the administration of angiotensin-convertingenzyme inhibitors and angiotensin II receptor blockerscan improve the properties of the skeletal muscles. Simi-larly, exercise training allows improvement in peak oxy-gen consumption, which parallels important biochemicaland histologic changes in the skeletal muscles. (CHF.2003;9:148–154) ©2003 CHF, Inc.

Ilaria Nicoletti, MD; Mariantonietta Cicoira, MD; Luisa Zanolla, MD; Lorenzo Franceschini, MD; Giovanna Brighetti, MD; Mara Pilati, MD; Piero Zardini, MDFrom the Dipartimento di Scienze Biomediche e Chirur-giche, Sezione di Cardiologia, Università degli Studi diVerona, Verona, Italy

Address for correspondence:Mariantonietta Cicoira, MD, Divisione di Cardiologia, Os-pedale Civile Maggiore, p. le Stefani, 1 37126 Verona, ItalyE-mail: mariantonietta.cicoira@univr.itManuscript received December 27, 2001;revised July 4, 2002;accepted August 12, 2002

Chronic heart failure (HF) is a common and debili-tating condition with high rates of mortality andmorbidity. The prevalence of symptomatic HF inthe general European population ranges from0.4%–2% and is expected to increase as the popula-tion ages.1 Commonly, symptom generation inchronic HF was attributed to central hemodynamicalterations, but other factors, such as skeletal mus-cle changes, may also play a role. The purpose ofthe present review is to summarize the availabledata on the widespread abnormalities which skele-tal muscle develops in the course of chronic HF,and to discuss how such alterations may be generat-ed and their role in the onset of the typical symp-toms of this condition.

The Hemodynamic HypothesisThe cardinal symptoms of HF are exercise intoler-ance and shortness of breath. For the last 40 years,physicians have considered disturbances of centralhemodynamics as the major determinants of symp-toms. According to this hypothesis, impaired leftventricular performance could lead to an excessiveincrease in pulmonary capillary pressure, which inturn may result in pulmonary congestion and pre-mature dyspnea, while an inadequate cardiac out-put could cause early fatigue secondary to poorskeletal muscle perfusion.2

From the Central Hemodynamic Factors to the PeripherySeveral studies3–6 have suggested that hemodynamicfunction does not accurately reflect the exercise ca-pacity or symptomatic status of patients with chronicHF. The correlation is poor between exercise intol-erance and resting central hemodynamic indexessuch as left ventricular ejection fraction,3 left ven-tricular end-diastolic dimension,4 cardiac index,5 orpulmonary capillary wedge pressure.6 In normalsubjects, exercise tolerance seems to be related to

Skeletal Muscle Abnormalities in ChronicHeart Failure Patients: Relation to Exercise

Capacity and Therapeutic Implications

cardiac output, whereas in patients with chronic HFcardiac output is not an important determinant ofexercise capacity, since exercise with arms and legsrather than legs alone results in a higher peak oxy-gen consumption (VO2peak) in chronic HF patients,but not in normal subjects.2 Furthermore, allinterventions which improve hemodynamic indexes(vasodilators,7 inotropic agents,8 cardiac trans-plantation,9 or repair of valvular stenosis,10) do not re-sult in an immediate increase in exercise tolerance;their beneficial effect appears only after weeks andsometimes months. These observations suggest that he-modynamic function is not deeply involved in symptomgeneration in chronic HF, and point toward the role ofperipheral factors, such as regional blood flow andskeletal muscle, as determinants of work capacity.

The Muscle HypothesisChronic HF is a multiorgan disorder initiated by a car-diac abnormality, such as a reduction in left ventricularfunction, which sets in motion a series of deleteriousevents that lead to wasting of skeletal muscle, markedby quantitative and qualitative alterations. However,there is no consensus on how this comes about.11

Etiology of Muscle Changes in Chronic HF. It is notclear whether skeletal muscle changes are primary (spe-cific myopathy) or secondary to a reduction in bloodflow to the exercising muscle due to: 1) abnormalities ofvasomotor tone; 2) reduced response to endogenous va-sodilatory stimuli, to infused hyperosmolar solutions,and to pharmacologic agents; 3) increased levels of en-dothelin; 4) reduced response to endothelial vasodilato-ry capacity or increased peripheral resistance (due to anincrease in the arterial wall sodium).2 Other possiblefactors responsible for skeletal muscle changes could bemalnutrition or malabsorption, although dietary sup-plementation fails to produce any improvement in mus-cle abnormalities or exercise capacity.12 Generalized ac-tivation of the sympathetic nervous system, seen earlyin the clinical course of the disease, could also con-tribute to muscle wasting through catabolic factors(tumor necrosis factor-α and insulin resistance), andloss of anabolic function.

Finally, inactivity has been proposed as a proba-ble determinant of muscle wasting; there are manysimilarities between the abnormalities of chronicHF and those seen in physical deconditioning. Inboth conditions, there is exercise intolerance, sym-pathetic hyperactivity, wasted skeletal muscles, de-creased fiber size, and depleted skeletal muscle ox-idative enzymes. Nevertheless, patients with disuseatrophy, unlike chronic HF patients, show a shifttoward the slow type of myosin heavy chains

(MHC).13 Therefore, although exercise training canreverse the muscle abnormalities in chronic HF,disuse alone cannot explain similar changes.

Ergoreceptors or Metaboreceptors. Piepoli et al.14

found strong significant correlations between ergore-flex activation and indices of exercise capacity, such asVO2peak and ventilation/carbon dioxide productionratio (VE/VCO2 slope), which led to their hypothesisthat the overactivity of muscle afferents could be relat-ed to the generation of symptoms which limit exercise.

Ergoreceptors consist of small myelinated or un-myelinated afferents arising from the skeletal mus-cle that travel in the lateral spinothalamic tract ofthe spinal cord.14 These receptors are overactiveduring exercise in chronic HF.15 Most likely theyare sensitive to metabolic changes related to musclework, such as potassium, adenosine, a decrease inpH, prostaglandins, blood flow itself, or lactate. Er-goreceptors modulate the hemodynamic, ventilato-ry, and autonomic response during exercise to meetthe augmented metabolic needs of the contractingmuscle.16 Their activation increases sympatheticoutflow, with a consequent increase in afterload anda decrease in blood flow to the periphery, furtherexacerbating skeletal muscle abnormalities. Onceactivated, the sympathetic nervous system may con-tribute to further catabolism of skeletal muscle anda progression of the deleterious cycle.11

Recently, it has been suggested that other fac-tors are also involved in the generation of abnor-mal responses to exercise in HF patients. One ofthese factors is probably an overactivity of periph-eral and central chemoreceptors17; nevertheless,the mechanism by which overactive chemorecep-tors cause an elevated ventilatory response to ex-ercise is not clear, because there is little fluctua-tion in arterial blood gases during exercise. In allprobability there is an interaction between ergore-flex and central chemoreflex; signals from muscleergoreceptors may feed directly into the respirato-ry control centers, causing central augmentationof both medullary and carotid chemoreceptorinput, or muscle ergoreceptors may inducechanges in central hypercapnic chemosensitivity.14

Alterations of Skeletal MuscleA myopathy develops in chronic HF that is charac-terized by histologic, biochemical, enzymatic, andfunctional alterations, which may return to normali-ty with appropriate therapy.

Muscle Bulk and Function. A common abnormalitypresent in patients with chronic HF is muscle atrophy,

CHF MAY/JUNE 2003SKELETAL MUSCLE AND HEART FAILURE 149

marked by a decreased fiber cross-sectional area.18,19

This muscle wasting could explain an impairment inmuscle function, which is expressed by a decrease inexercise tolerance. Despite a reduction in muscle bulk,some studies have found preservation of musclestrength,20 whereas others have reported reducedskeletal muscle strength.21–23 Moreover, only a weakcorrelation has been found between muscle size anddynamic endurance; therefore the impairment of en-durance might be explained by both qualitative andquantitative alterations in the skeletal muscle of pa-tients with chronic HF.18

Histologic Alterations. Many authors have observed ashift from slow-twitch type I fibers to fast twitch type IIfibers, that have higher oxygen and adenosine triphos-phate consumption.23–28 Details of muscle changes areshown in the Table. The fast, more fatigable type IIfibers reach anaerobic metabolism earlier; clinically,this causes the earlier onset of exercise intolerance anddyspnea. Such alterations can be reversed by an effec-tive therapy. In a recent study Vescovo et al.29 reporteda reshift of MHCs of leg skeletal muscle toward theslow, more fatigue-resistant isoforms, after treatmentwith losartan and with enalapril. Such reshift is associat-ed with a similar improvement in exercise tolerance,thus confirming that there may be a strong relationshipbetween muscular biochemical changes and the clinicaland functional status of patients with chronic HF.

Ultrastructural morphology of skeletal muscleseems to be further altered by the presence of an in-creased number of apoptotic myocytes, which areprobably responsible for loss of muscle bulk. Severalgenes which are known to be potent regulators ofapoptosis are altered: particularly, dominant onco-genes such as c-myc or bcl2 are reduced, whereas thetumor suppressor gene p53 and other factors that seemto favor apoptosis (inducible nitric oxide synthase, ni-tric oxide, caspase-3, ubiquitin) are overexpressed.30

These observations suggest that apoptosis occurs inskeletal muscle myocytes, and it has been demonstrat-ed that this alteration is strongly related to exercise in-tolerance in patients with chronic HF.30

Muscle Metabolism. Histologic changes are associ-ated with biochemical alterations, expressed by areduction in oxidative enzymes26 and an impair-ment of fatty acid metabolism, expressed by lowconcentration of skeletal muscle long chain acyl-carnitine, increased lipid droplets, and reductionof β-hydroxyacyl coenzyme A dehydrogenase, anenzyme involved in β-oxydation of fatty acids.23

Furthermore, as measured by phosphorus-31 nu-clear magnetic resonance in patients with chronicHF, phosphocreatine decreases during exerciseand its recovery is delayed while inorganic phos-phate and adenosine diphosphate increase and pHfalls more than in healthy controls.31–33

CHF MAY/JUNE 2003150 SKELETAL MUSCLE AND HEART FAILURE

Table. Histologic and Metabolic Abnormalities in the Skeletal Muscles of Chronic Heart Failure Patients

AUTHORS

NO. OF

PATIENTS

MUSCLE

GROUPS

FIBER TYPE

I IIA IIB IIC

CAPILLARY

/FIBER /MM2

KREBS

CYCLE

LIPID

OXIDATION

OTHER

ABNORMALITIES

Manciniet al.24

22 Gastrocnemius ↔ ↓ ↑ ↑ ↔ ↑ ↔ ↓

Sullivanet al.26

11 Vastus lateralis ↓ ↔ ↑ ↔ ↓ ↔ ↓ ↓

Drexleret al.27

57 Vastus lateralis ↓ ↑* ↓ ↓ ↓Vvm, ↓Svmc

Lipkinet al.28

9 Quadriceps ↓ ↑* ↔ ↑LD

Vescovoet al.25

19 Gastrocnemius ↓ ↑ ↑

Dunnigamet al.23

22 Cardiac andskeletal muscle

↓ Interstitialfibrosis; dilatedSR; ↑n° ofintercalateddiscs; ↑LD

Vvm=volume density of mitochondria; Svmc=surface density of mitochondrial cristae; LD=lipid deposits;SR=sarcoplasmatic reticulum; *data are given for all type II fibers

Such metabolic alterations play a role in theearly onset of anaerobic metabolism and hence inthe pathophysiology of exercise intolerance.34 Ear-lier intramuscular acidosis has been related both topump failure and to reduced blood flow during ex-ercise.35 However, several studies have suggestedthat this metabolic response to exercise in chronicHF is also a result of intrinsic muscle abnormalities.Although cardiac output and leg blood flow im-prove with hydralazine or with dobutamine, lactateproduction increases in the exercising muscles ofpatients with chronic HF. Moreover, even chronicHF patients with normal leg blood flow, comparedwith others with chronic HF, have an abnormal lac-tate release during exercise.34,36

Skeletal Muscle Alterations and Exercise Toler-ance. Muscle alterations might be responsible for areduction in functional performance and in theclinical status of patients with chronic HF. This isconfirmed in a study by Vescovo et al.,37 whichdemonstrated that the magnitude of the shift fromslow aerobic to fast glycolytic and fast oxidative iso-forms correlated with both functional and objectivemeasurements of exercise capacity (VO2peak; oxygenpulse VO2peak; ventilatory threshold). In fact, thereis a positive correlation between VO2, ventilatorythreshold, oxygen pulse, and the percentage ofMHC I, whereas the correlation is negative withMHC II. A high proportion of glycolytic fibers re-duces exercise capacity, because of early anaerobicmetabolism. These data are consistent with the hy-pothesis that exercise tolerance in patients withchronic HF is limited by skeletal muscle metabo-lism, which is in turn an expression of muscle fibertype. The fast fibers are more fatigable and there-fore contribute to exercise intolerance in patientswith chronic HF.

Symptoms and Indices of Exercise Capacity. Car-diopulmonary exercise testing is an objective and use-ful means of determining the clinical and functionalcapacity of patients with chronic HF. Symptoms areassociated with reduced indices of exercise tolerance(VO2peak, exercise duration) and with elevated ventila-tory response (VE/VCO2).15 In fact, for a given rate ofcarbon dioxide production, patients with chronic HFventilate at a higher level compared with normal sub-jects; therefore, the slope relating minute ventilationto carbon dioxide output (VE/VCO2 slope) during ex-ercise is steeper in patients with chronic HF.38 More-over, VE/VCO2 slope is inversely related to VO2peakand both are independent prognostic markers.39 Usu-ally an excessive ventilatory response to exercise is at-tributed to increased dead space/tidal volume ratio,

secondary to a ventilation-perfusion mismatch,40,41 topulmonary vasoconstriction,42 or to augmentedchemoreceptor sensitivity.38 It has also been estab-lished that patients with chronic HF have little fluctu-ation in arterial blood gases, both at rest and duringexercise,43 so it is not likely that a primary lung ab-normality could result in excessive ventilation, with-out alterations of blood gases as a signal.

Dyspnea and increased ventilation could becaused by abnormalities of respiratory muscle simi-lar to those seen in other skeletal muscles. Further-more, it has recently been suggested that there maybe some link between muscle abnormalities and theexaggerated ventilatory response to exercise viamuscle ergoreflex.36 Consequently we can assessthat the two symptoms causing exercise limitation,fatigue and dyspnea, are reflections of a single un-derlying physiologic process.44

VO2peak is a useful and objective index of exer-cise capacity and a strong independent predictor ofsurvival in chronic HF. Mancini et al.45 recom-mended a threshold of VO2peak of 14 mL/min/kg toclassify chronic HF patients as at risk and to estab-lish timing for cardiac transplantation. Subse-quently, other investigators sought further refine-ments in this particular criterion and other gas ex-change variables were evaluated for their predic-tive power, including percent predicted VO2peak

46

or VE/VCO2 production ratio.47

It has been established that skeletal muscle massis an important determinant of exercise capacityand an independent predictor of VO2peak andVE/VCO2 slope. Total fat mass is also an indepen-dent predictor of VO2peak; particularly, the relationbetween VO2peak and lean mass is positive (Figure1), whereas the relation between VO2peak and fatmass is negative, i.e., the higher the fat content, thelower the exercise capacity.48 The relation betweenlean mass or fat mass and VO2peak occurs becauseduring exercise, oxygen is consumed almost exclu-sively by working muscles, whereas fat mass essen-tially consumes no oxygen. This relation explainswhy usually there is a difference between womenand men in VO2peak and exercise tolerance, whereasthis difference does not exist when VO2peak is cor-rected for lean mass (Figure 2).

Considering the strong relation between leanmass and VO2peak, we might think it possible to im-prove the prognostic value of VO2peak by correctingthis parameter only for skeletal muscle mass insteadof for total body weight. A recent study by Osman etal.49 demonstrated that this correction would moreaccurately define functional status and clinical out-come in a population of 225 patients with chronicHF, especially in women and the obese.

CHF MAY/JUNE 2003SKELETAL MUSCLE AND HEART FAILURE 151

Potential Therapeutic InterventionsKnowledge of the strong relationship betweenskeletal muscle and exercise capacity has suggestednew strategies for intervention. Muscle wasting re-sults in activation of the sympathetic nervous sys-tem, which both directly and indirectly determinesfurther deterioration in skeletal muscle. Ratherthan treating the consequences of this vicious cycle,therapeutic interventions should interrupt it, atleast partially. All interventions which improve he-modynamic abnormalities may alleviate the symp-toms, but don’t reduce the risk of disease progres-sion,50 whereas pharmacologic agents that blockneurohormonal and renin-angiotensin systems notonly improve the patient’s quality of life, but alsoreduce cardiovascular morbidity and mortality. Arecent study,51 demonstrated that the angiotensin IItype I receptor blocker irbesartan can prevent my-ocyte apoptosis, muscle atrophy, and changes inMHCs in experimental HF. Probably the effect ofthis drug is to interfere with tumor necrosis factor-αand angiotensin II, which exert a proapoptotic role.Since the realization that long-term activation of thesympathetic nervous system may be deleterious tothe heart, there has been increasing interest in theuse of β blockers in the treatment of HF.50 More-over it has been found that patients with chronicHF have elevated levels of growth hormone, but lowlevels of insulin-like growth factor I,52 thus suggest-ing there may be a growth hormone resistance syn-drome,53 which probably plays a role in the devel-opment of muscle bulk loss and cachexia in chronicHF. Overcoming growth hormone resistance mightbe an alternative therapeutic intervention to pre-vent/reverse cardiac cachexia and skeletal musclewasting in chronic HF.

Physical Training. Several studies have demon-strated that regular exercise training exerts benefi-cial effects on the ultrastructural morphology andoxidative capacity of skeletal muscle: the total vol-ume density of mitochondria and the volume densi-ty of cytochrome-c oxidase-positive mitochondria,capillary density, and fiber size all increased.54 Thesechanges are accompanied by metabolic consequencessuch as slow utilization of muscle glycogen, a greaterreliance on fat oxidation, and less lactate productionduring exercise. Studies using phosphorus-31 nuclear

CHF MAY/JUNE 2003152 SKELETAL MUSCLE AND HEART FAILURE

Figure 1. Representation of the linear relationship betweenpeak oxygen consumption (VO2peak) and total lean mass in apopulation of ambulatory chronic heart failure patients

Figure 2. Representation of differences in exercise capacitybetween men and women with chronic heart failure. PanelA demonstrates that peak oxygen consumption corrected bybody weight (VO2peak-W) significantly differs between menand women. Panel B demonstrates that peak oxygen con-sumption corrected by total lean tissue (VO2peak-L) does notdiffer between the two genders.

p<0.001

p=NS

magnetic resonance55 have demonstrated that physi-cal training significantly reduced phosphocreatinedepletion and the increase in adenosine diphosphateduring exercise, while it did not change the pH re-sponse during exercise, probably because both phos-phocreatine depletion and lactic acid production de-creased after training. These changes in muscle me-tabolism determine a lower production of thosemetabolites that activate ergoreceptors and hence im-prove the exercise capacity.56

Exercise training programs can improve cardiacperformance, but the majority of their effects areseen in the periphery. There may be an improve-ment in exercise tolerance in patients with chronicHF through peripheral mechanisms, e.g., by delay-ing the onset of anaerobic metabolism.57 The re-duction in leg vascular resistance determines an in-creased leg blood flow, a decrease in the rise in lac-tate levels during exercise, an increase in the venti-latory anaerobic threshold, and a decrease in theventilatory response to exercise.58

The relationship between skeletal muscle massand exercise capacity suggests that VO2peak mightincrease after interventions directed toward increas-ing skeletal muscle bulk. In the future it may bepossible to improve skeletal muscle function notonly with exercise training but also through phar-macologic interventions, perhaps with anabolicsteroids or with β2 adrenoceptor antagonists,59 oreven with human growth hormone.60

ConclusionsIn this review we intended to consider the changes inskeletal muscle in chronic HF, and their relation to theclinical and functional status of patients. The increas-ing importance attributed to peripheral factors seemsto offer new possibilities for the understanding of thepathophysiology and treatment of chronic HF syn-drome. Therapeutic approaches focusing on musclechanges and the mechanisms responsible for their gen-eration may help to improve the quality of life and thepoor prognosis associated with this debilitating disease.

Acknowledgments: The authors wish to thank Ms. Christine Harrisfor revising the English manuscript.

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