implications of chronic heart failure on peripheral vasculature and skeletal muscle before and after...

7/30/2019 Implications of Chronic Heart Failure on Peripheral Vasculature and Skeletal Muscle Before and After Exercise Traini

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Implications of chronic heart failure on peripheral vasculatureand skeletal muscle before and after exercise training

Brian D. Duscha P. Christian Schulze Jennifer L. Robbins Daniel E. Forman

Published online: 23 October 2007

Springer Science+Business Media, LLC 2007

Abstract The pathophysiology of chronic heart failure

(CHF) is typically conceptualized in terms of cardiac dys-function. However, alterations in peripheral blood flow and

intrinsic skeletal muscle properties are also now recognized

as mechanisms for exercise intolerance that can be modified

by therapeutic exercise. This overview focuses on blood

delivery, oxygen extraction and utilization that result from

heart failure. Related features of inflammation, changes in

skeletal muscle signaling pathways, and vulnerability to

skeletal muscle atrophy are discussed. Specific focus is

given to the ways in which perfusion and skeletal muscle

properties affect exercise intolerance and how peripheral

improvements following exercise training increase aerobic

capacity. We also identify gaps in the literature that mayconstitute priorities for further investigation.

Keywords Vascular Skeletal muscle

Capillary density Muscle fiber Mitochondria

Inflammation Apoptosis Ubiquitin ligase

Exercise training

Introduction

Pathophysiology of systolic chronic heart failure (CHF)

entails an initial injury to the heart that results in decreased

left ventricular (LV) function and progressive declines in

cardiac output. Eventually, pump function is inadequate to

supply sufficient blood perfusion for systemic metabolic

needs. Clinical consequences can include dyspnea, fatigue,

and exercise intolerance. However, over two decades of

research have demonstrated that exercise intolerance in

CHF is very complex and also extends to systems and

abnormalities beyond the heart. Among its systemic

effects, CHF has detrimental impact on local blood flow

and skeletal muscle oxidative metabolism. In particular,

skeletal muscle is a major determinant of exercise intol-

erance and subsequent disability. Decreased oxygen

delivery (abnormal peripheral blood flow/muscle perfu-

sion) and changes in extraction/utilization by muscle affect

exercise tolerance. Exercise training induces adaptations

that have proved beneficial for increasing functional

capacity and improvements in skeletal muscle that have

been implicated in explaining much of these benefits. This

article will focus on the known alterations to peripheral

blood flow and skeletal muscle in patients with CHF. In

addition, it will describe how exercise training

B. D. Duscha J. L. Robbins

Duke University Medical Center, Box 3022, Durham

NC 27710, USA

B. D. Duscha

e-mail: [email protected]

J. L. Robbins


P. C. Schulze

Division of Cardiology, New York Presbyterian Hospital,

Columbia University Medical Center, 622 West 168th Street, PH

3-347, New York, NY 10032, USA


D. E. Forman (&)

Brigham and Womens Hospital, 75 Francis Street, Boston, MA

02115, USA


D. E. Forman

Veterans Administration Medical Center (VAMC) of Boston,

Boston, MA, USA

D. E. Forman

Harvard Medical School, Boston, MA, USA

123

Heart Fail Rev (2008) 13:2137

DOI 10.1007/s10741-007-9056-8


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interventions have improved skeletal muscle and functional

capacity. Throughout this article an attempt will be made to

identify gaps in the literature and suggest future directions

for investigation.

Interplay between cardiac output, hemodynamics,skeletal muscle, and exercise tolerance

The Fick equation states that maximal oxygen consumption

can be calculated as the product of cardiac output (stroke

volume heart rate) multiplied by A-VO2 difference (the

capacity of peripheral tissue to utilize oxygen). It makes

clear that functional capacity depends both on central

cardiac performance as well as on peripherally mediated

oxygen utilization. However, potential to increase cardiac

output is inherently limited by heart failure [1], that is,

hearts of CHF patients tend to be maximally dilated even at

baseline, such that it is less likely that functional gains canbe achieved by additional myocyte growth adaptations to

increase stroke volume through principles of the Starling

mechanism. Likewise, CHF patients have limited chrono-

tropic and inotropic reserves, with inherently reduced

capacity for functional gains to be achieved by increasing

heart rate and/or contractility. Therefore, for CHF patients

on maximal medical therapy, peripheral adaptations that

increase A-VO2 differences through exercise training are

the mechanisms best suited to enhance functional capacity

and clinical performance in spite of the constraints of

disease.

A large body of literature has contributed to an evolu-tion of insights regarding central versus peripheral

mechanisms underlying functional capacity and symptoms

among CHF patients. Key principles include the following:

(1) there is little correlation with resting central hemody-

namic indices and peak oxygen consumption in CHF; (2)

acutely improving blood delivery does not lead to

improved exercise tolerance in CHF; and (3) decondition-

ing does not completely explain differences in exercise

capacity. Major examples include the following:

1. Studies in which measurements of low LV ejection

fraction and increased pulmonary wedge pressures do

not relate to exercise intolerance in CHF. The analyses

also show that resting LV hemodynamic indices (such

as LV end diastolic dimension, mean velocity of

circumferential fiber shortening, and ratio of pre-

ejection period to LV ejection time) are unrelated to

exercise capacity or symptom status in CHF [24].

2. Studies in which acute use of inotropes and vasodila-

tors do not translate into increases in exercise

tolerance, despite improving leg blood flow (LBF)

and cardiac output. Following these pharmacologic

therapeutic agents, CHF patients still experience early

onset of lactate accumulation and early anaerobic

metabolism [57].

3. Studies showing that exercise training improves lactate

threshold, but without significantly improving cardiac

output in CHF [8].

4. 31P-MRI studies showing early anaerobic metabolism

in CHF both in the presence of normal LBF and afteroccluding skeletal muscle blood flow [912].

5. Studies demonstrating intrinsic abnormalities in skel-

etal muscles in CHF patients, compared to aerobically

matched sedentary normal controls [13] as well as to

other diseased populations with normal ventricular

function and disuse atrophy [14]. Furthermore, animal

models suggest CHF results in changes in skeletal

muscle gene expression at the pre-translational level

that cannot be accounted for by inactivity [15].

LBF during exercise

When exercising, skeletal muscle demands greater blood

and oxygen supply than at rest. In healthy normal adults, up

to 85% of the total blood flow is directed toward active

skeletal muscle in working limbs [16], with flow to leg

muscles usually receiving the greatest increases in flow.

Arterioles dilate and cardiac output augments to increase

peripheral flow. Usually arteriolar vasodilation and capil-

lary volume can readily facilitate and accommodate the

high volume of blood that is needed to sustain working

muscle. However, at high workloads, the hearts capacity

to supply blood and oxygen is eventually exceeded. Sym-

pathetically mediated vasoconstriction maintains vascular

tone and preserves hemodynamic equilibrium even at high

workloads, tempering any exercise-induced vasodilating

effects [17].

In contrast, vasoconstriction is increased among CHF

patients relative to normal at rest and with exertion, con-

tributing to reductions in LBF, and thereby lessoning sub-

maximal and maximal work capacities [1821] (Fig. 1).

Overall, LBF falls due to the combined effects of low

cardiac output, increased leg vascular resistance, and

abnormal arteriolar constriction [19, 22, 23].

Increased vasoconstriction stems, in part, from the

effects of heightened sympathetic output in CHF. This is

compounded by the impaired release of several vasoactive

substances from the endothelium that additionally

encumber vasodilatory responses. Normally, endothelial

cells along the lumen of large conduit arteries secrete

nitric oxide (NO), a potent vasodilator, in response to

mechanical shear stress. However, chronic reductions in

peripheral blood flow secondary to decreased LV function

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impair the release of endothelial NO that normally occurs

via this mechanism [2426]. Vascular smooth muscle

responsiveness to NO is also reduced in patients with

CHF, further undercutting NO-mediated vasodilation

[27, 28]. In addition, prostaglandins may inhibit agonist-

mediated NO vasodilation in the periphery [29]. Two

powerful vasoconstrictors, angiotensin II and endothelin-

1, are elevated in patients with CHF, which further con-

tribute to the abnormal regulation of vascular tone

[3032].

Among the many studies that have demonstrated the

significance of vascular physiology in CHF, some of the

most compelling data have come from studies comparing

one-legged versus two-legged exercise. Compared to two-

legged exercise, one-legged exercise in patients with CHF

demonstrates higher LBF, lower leg vascular resistance,

and lower central A-VO2 at both submaximal and peak

exercise. However, regardless of whether one- or two-

legged exercise is performed, mean arterial pressure

(MAP) is preferentially preserved at the expense of leg

hypoperfusion [20, 22]. Another key insight relates to the

fact that even with relatively higher LBF during one-legged

exercise, lactate accumulation is unaltered [19, 33]. In

aggregate, these studies highlight the complexity of exer-

cise intolerance and the intricate interplay between central

and peripheral mechanisms.

Beyond LBF: intrinsic skeletal muscle limits exercise

Patients with CHF compensate for reduced LVF with an

increased A-VO2, such that resting and sub-maximal

exercise oxygen consumption are similar to that of nor-

mals. Despite this increase in A-VO2, CHF patients have

increased lactate production, even during sub-maximal

exercise [6, 18, 19, 34] (Fig. 1). Early blood lactate pro-

duction is a function of intramuscular acidosis and not

reduced lactate clearance [9, 10]. This finding suggests that

intrinsic skeletal muscle abnormalities are responsible for

early anaerobic metabolism.

Fig. 1 Resting and exercise

single leg blood flow, leg

vascular resistance, leg

arteriovenous oxygen

difference, single leg VO2,

femoral venous oxygen content

and femoral venous oxygen

saturation in patients with

chronic heart failure (n = 30)

(O) and normal subjects

(n = 12) (d); *p\ 0.05,

p\ 0.01 patients versus normal

subjects. Dashed lines indicate

inter-group comparisons of

maximal data (Reprinted with

permission from reference 19)

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Interestingly, acute usage of peripheral vasodilators or

ACE inhibitors lead to immediate improvements in

peripheral vessel dilation and LBF without an immediate

increase in peak VO2 [6]. It is hypothesized that 2

3 months of increased LBF (due to pharmacological ther-

apy) may be necessary to induce changes in intrinsic

skeletal muscle [35]. This would explain why peak VO2

increases only after several months of the greater LVfunction achieved with medical therapy [35, 36]. Similarly,

it seems likely that prolonged decreases of LV function

cause skeletal muscle abnormalities. Nonetheless, it is also

possible that these skeletal muscle changes may be inde-

pendent of LV function.

Perhaps the most convincing work was done by Wilson

et al. [12] who identified CHF patients with normal LBF

during exercise but reduced leg oxygen consumption and

early lactate production. While a separate study by Wilson

et al. [7] demonstrated immediate improvement in LBF

using dobutamine, concomitant improvements in lactate

response at a given workload were not similarly elicited.Other investigators [9, 11] have also demonstrated abnor-

mal skeletal muscle metabolism under ischemic conditions,

unrelated to LBF.

Capillary density and intra-muscle oxygen dynamics

Microcirculation of skeletal muscle constitutes another

important dimension of vascular flow dynamics pertinent

to CHF, especially since it is a critical juncture between

vascular flow dynamics and intrinsic properties of skeletal

muscle that affects exercise performance. The primary

function of the capillary bed in skeletal muscle is to supply

oxygen to muscle fibers. In the same way that contractile

protein composition and mitochondrial mass are important

factors in skeletal muscle physiology, relative vascular

density is higher in oxidative, fatigue-resistant muscles

compared with glycolytic muscle. A key benefit of exercise

training is that it induces increased capillary density, which

constitutes a primary mechanism by which skeletal muscle

can adapt to achieve higher A-VO2 differences and related

functional enhancements.

For this article we identified seven studies that evaluated

capillary density in CHF patients compared to healthy

controls. The comparisons reveal significant variance

between analyses. When capillary density was measured as

the ratio of capillaries per muscle fiber, six of the seven

studies reported reduced capillary density (ranging from

17% to 32%) in the skeletal muscle of CHF patients [33,

3741]. Within this group of studies, only one used

endothelial cell specific staining (versus a total basement

membrane stain). This was also the study that showed the

highest difference of capillary density (32%) [37] in CHF

versus normals, and was the only study that demonstrated

that capillary density in CHF correlated to exercise per-

formance (peak VO2 and exercise time).

In contrast, when capillarity density was analyzed as

capillaries per area (mm2), only one of six studies showed

reduced capillary density in CHF patients compared to

normal controls. One study even showed an increase in

capillary density in CHF patients [42]. The discrepanciesbetween studies attest to the importance of fiber size when

completing capillary density assessments.

In general, when measuring capillary density as capil-

laries per fiber, CHF patients have lower capillary density

than normal healthy adults. Moreover, when analyzing

capillary and functional capacity across a continuum of

fitness levels or when combining healthy controls and CHF

patients, it is possible to demonstrate that capillary density

relates to peak VO2. However, when analyzing only CHF

patients, it has been difficult to reproduce this relationship

between capillary density and functional capacity. Given

this ambiguity, it seems that the interplay between capil-larity and performance may parallel the issues that

pertained to LBF and skeletal muscle metabolism in CHF.

Regardless of whether or not microcirculation increases,

oxygen uptake may initially lag based upon the capacity of

skeletal muscle to extract and utilize the oxygen it receives

(i.e., due to decreased oxidative machinery such as mito-

chondria and enzymes).

Consistently, blood drawn from the vasculature draining

working muscles during exercise has been demonstrated to

show less than 1 ml of O2/100 ml of blood in patients with

both cardiovascular disease [43] and heart failure [19], a

relationship that cannot acutely change to achieve greater

A-VO2 differences. It is possible that increases and

decreases in capillary density may be regulated by the

muscles need to extract and utilize oxygen. This concept is

demonstrated among normal adults by Andersen [44] in

work which showed that as muscle blood flow increases

linearly with exercise workload, the vascular bed can

readily accommodate higher flow, but oxygen utilization

becomes limited by mitochondrial enzymes. Likewise,

Saltin et al. [45] assert that increases in capillary volume is

not induced by a drive to accommodate larger blood flow,

but rather to optimize the surface area required for the

exchange of oxygen, substrate, and metabolites.

Future research on oxygen flux from the red blood cells in

the capillary to the muscle is necessary to understand the

relationship between microcirculation and skeletal muscle

oxidative metabolism. This line of investigations would help

to determine the functional importance of capillary density in

the skeletal muscle of CHF, with focused attention on fiber

types, fiber atrophy, oxygen diffusion, and timeline

relationships to other intrinsic oxidative markers before and

after interventions and as CHF severity progresses.

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Many believe that endothelial health may play a key role

in complex interrelationships between capillarity, oxygen

delivery, and clinical benefits. A number of growth factors

have been implicated as mediators for the growth and

proliferation of endothelial cells (angiogenesis). The

growth factor receiving the most attention has been vas-

cular endothelial growth factor (VEGF). Despite this

interest, the impact VEGF has on skeletal muscle andfunctional capacity is poorly understood. Most studies have

been limited to animal models or to the myocardium, with

few focusing on human skeletal muscle or exercise inter-

ventions. Animal models have shown that VEGF mRNA

and protein expression is increased in skeletal muscle that

is more oxidative versus glycolytic and muscle that is

subjected to increases in contractile activity [46, 47].

Vascular endothelial growth factor unquestionably plays a

role in angiogenesis. Therefore, it would seem logical to

think that the amount of skeletal muscle VEGF can predict

capillary density values but, in fact, no clear relationship

has been proven. Gustafsson [48] showed that after8 weeks of one-legged knee extension training that both

VEGF at the mRNA and protein levels were increased

approximately two times in CHF patients. Unfortunately,

capillary density was not measured in this study. It is

possible that hypoxia [49], induced by exercise, creates a

stimulus for VEGF expression.

The difficulty of studying VEGF is further complicated

by the fact that it has multiple isoforms and receptors. The

VEGF receptor VEGFR1 is a soluble form that is believed

to have a higher affinity for VEGF than VEGFR2. In

addition, VEGFR1 and VEGFR2 are part of different sig-

naling pathways that play separate downstream roles in the

regulation of angiogenesis, apoptosis, and NO. How VEGF

and potentially other growth factors are affected by CHF,

how responsive VEGF is to exercise training, and how

VEGF affects other oxidative skeletal muscle characteris-

tics (capillary density and oxidative enzymes) and

functional capacity remain compelling areas of research.

Intrinsic skeletal muscle abnormalities and reduced

oxidative capacity in CHF

Although the characteristics of skeletal muscle represent a

continuum across fitness levels [17, 5052], numerous

studies report a phenotypical shift from oxidative (red) type

I fiber type to more glycolytic (white) type II skeletal

muscle fiber types in CHF, with these changes rooted in

disease pathology and not merely due to exercise decon-

ditioning [13, 14]. This pattern of change appears to affect

all characteristics of skeletal muscle including enzymes,

mitochondria, capillary density, and the propensity to

atrophy. These intrinsic changes correlate to decreased

oxidative metabolism and to increased muscle weakening

and fatigability that are at least partially reversible by

exercise training.

While the predominant shifts in skeletal muscle were

initially discovered by muscle biopsy, confirming data have

been collected using 31P magnetic resonance spectroscopy

(MRS). MRS studies have shown abnormal phosphocrea-

tine (PCr) and ATP metabolism leading to early anaerobicmetabolism during exercise [5356] and recovery from

exercise [57]. Furthermore, MRS showed that oxidative

metabolism was improved following exercise training

[53, 58, 59].

Relative change of fiber types

Overall, it is well accepted that CHF patients have a lower

percentage of oxidative skeletal muscle compared to nor-

mal controls and that these alterations are partially

responsible for the observed exercise intolerance and fati-gue. Studies report 1020% decreases in oxidative type I

fibers in CHF patients with increases in glycolytic type IIb

fibers compared to normals [33, 38, 40, 42, 60]. These

shifts have been correlated to peak VO2 [42] and leg fati-

gue during isokinetic knee extension [38]. Related studies

confirm these relationships by demonstrating reduced

myosin heavy chain (MHC) type I isoforms with reduced

peak oxygen consumption and lower functional class in

CHF [61, 62]. Furthermore, a series of studies indicate that

many aspects of CHF skeletal muscle abnormalities can

adapt to aerobic exercise training with restoration of more

normal intrinsic properties (Table 1).

Interestingly, Sullivan [62] also demonstrated that three

of nine CHF subjects had no MHC type I, an abnormal

discovery for any population, suggesting that there are

fundamental differences in gene expression with CHF

pathophysiology. Vescovo [14] also demonstrated MHC

alterations specific to CHF when compared to disuse

atrophy following patients who have suffered a stroke. The

latter two examples point toward a disease-specific

pathology or a molecular mechanism unique to CHF.

Enzymes

Although glycolytic enzymes appear to be unchanged (or

slightly increased) in CHF, oxidative enzymes are

decreased [13, 33, 37, 38, 40, 42, 63, 64]. Historically,

studies have measured enzymes of the Krebs Cycle and b-

oxidation. Specifically, mitochondrial enzymes (citrate

synthase and succinate dehydrogenase) and enzymes

involved in b-oxidation of fatty acids (3-hydroxyl CoA

dehydrogenase) have been shown to be decreased [33].

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Furthermore, Sullivan et al. [65] found inverse relation-

ships between oxidative enzyme activity and blood lactate

accumulation during sub-maximal exercise. Interestingly,

in this study CHF patients had less PCr depletion and

lactate accumulation at peak exercise than normals, raising

the possibility that intrinsic skeletal muscle abnormalities

may be responsible for early anaerobic metabolism.

Drexler et al. [40] also demonstrated a close relationshipbetween cytochrome c oxidase, mitochondrial volume

density or cristae surface density and peak VO2. To further

strengthen a rationale that oxidative enzymes play an

important role in exercise capacity, others have also

demonstrated relationships between citrate synthase and

peak VO2 [38, 66].

Mitochondria

In healthy individuals, the most important determinant inmaximal oxygen consumption is the delivery system

(cardiac output) [67], whereas sub-maximal indices rely on

skeletal muscle (mitochondria content and other oxidative

machinery) [68]. However, in CHF, due to a compromised

delivery system, characteristics of skeletal muscle become

relatively more important. Mitochondria generate most of a

cells ATP and therefore play an intricate role in skeletal

muscle energy metabolism. Surprisingly, we identified

only one study that directly measured mitochondria com-

pared to a healthy control group. This study by Drexler

et al. [40] demonstrates that oxygen consumption corre-

lates to reduced mitochondrial volume and surface area.Most CHF studies have chosen to measure mitochondrial

enzymes as a surrogate of mitochondria versus direct his-

tochemical analysis. A decline in mitochondrial number

and size indicates a reduced oxidative capacity of the

muscle and has been offered as an explanation for the rapid

fatigue that occurs in patients with CHF. Among the fac-

tors contributing to the mitochondrial defects seen in the

skeletal muscle of CHF patients are increased production

of toxic mitochondrial reactive oxygen species and alter-

ations in mtDNA number or mutations. Toxic intracellular

levels of NO produced by iNOS may also impair oxidative

phosphorylation [69].

Increased inflammation and CHF

The extensive effects of CHF on skeletal muscle, capillar-

ity, and other constitutive aspects of local architecture and

function have led to consideration of underlying factors that

may change fundamental molecular signaling patterns.

CHF entails predominant changes in inflammation andTable1

continued

Study

Subjectnumber(Ex/Cntl)Duration

Training

mode

TrainingRx

Intrinsicskeletalmusclefindings

Magnussonetal.[125]

5/6

8weeks

Onelegged

dynamicknee

extension

6575%45min/

3daysaweek

Capillaryperfiberratioincreasedby47%.Citratesynthase

wasincreasedby77%,HADinc

reasedby53%,and

LDHdidnotchangewithtrainin

g.

Gordonetal.[156]

14/7(2traingroups)

8weeks

Oneleggedandtwolegged

kneeextensors

35%and6575%

15min/3days

aweek

Citratesynthaseincreasedby23%

intheonelegged

traininggroupandby35%inthetwoleggedtraining

groupwhilePFKremainedunchangedineithergroup

Hambrechtetal.[25]

12/10

6months

Bike

70%4060min/day

Changesincytochromec

oxidase(+

)mitochondria(:41%)

werelinkedtoimprovementinp

eakoxygen

consumptionatventilatorythresh

old.Totalvolume

densityofmitochondriaincreasedby19%

Belardinellietal.[124]18/9

8weeks

Bike

40%30min/3

daysaweek

Trainingincreasedcapillarydensity

slightly(5%)butwas

reducedperfiber(9%).Fibertypingwasunchangedwith

training.Highcorrelationbetwee

nchangesinvolume

densityofmitochondriaandchangesinpeakoxygen

consumptionandlactatethreshol

d

Heart Fail Rev (2008) 13:2137 27

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growth regulating peptides that may factor into these criti-

cal processes.

Specifically, CHF stimulates an imbalance of catabolic

over anabolic molecules [70]. TNF-a, IL-1b, and iNOS

[71] all increase and contribute to skeletal muscle

derangements. TNF-a induces catabolic metabolism,

reduced skeletal muscle contractility, and ultimately mus-

cle atrophy. IL-1b suppresses expression of thesarcoplasmic reticulum Ca2+ ATPase (SERCA) and phos-

pholamban [72]. Other factors like sphingosine and iNOS

have also been proposed as potential mediators of the

negative inotropic actions [73].

NF-jB is a transcription factor that regulates the

expression of proinflammatory cytokines especially in

combination of oxidative stress. Muscle activity and

ischemia likely add to this process [74, 75]. Intracellular

accumulation of NO generated by iNOS may produce

toxic levels of NO high enough to inhibit key enzymes of

the oxidative phosphorylation either directly through post-

translational protein modification by NO (-S-nitrosylation)or indirectly through formation of reactive NO metabo-

lites [76]. Therefore, elevated iNOS is linked to

diminished citrate synthase and other indices of oxidative

metabolism. Furthermore, inflammation catalyzes proteo-

lytic pathways, such that apoptosis, ubiquitin proteasome

proteolysis, and other key avenues toward muscle atrophy

are accelerated.

Effects of inflammation and reduced IGF-1 on skeletal

muscle

Dysregulation of growth hormone (GH) and insulin-like

growth factor-1 (IGF-1) signaling is a key consideration in

the pathophysiology of CHF. Catabolic syndromes in

chronic inflammation, sepsis, or cancer show an altered

state of the GH/IGF-1 axis due in part to peripheral IGF-1

deficiency and also because of an impaired IGF-1 response

to GH [77, 78]. Elevated levels of GH with inappropriately

normal serum levels of IGF-1 have been described in

cardiac cachexia [79]. This has been attributed in part to

increased serum levels and the local expression of proin-

flammatory cytokines such as IL-1b and TNF-a [80].

Consistently, low levels of systemic IGF-1 are associated

with decreased leg muscle cross-sectional area (CSA) and

strength [81].

It is especially notable that a significant proportion of

IGF-1 is produced locally by muscle fibers and then acts

as a paracrine, rather than endocrine, regulator of

skeletal muscle hypertrophy or atrophy. It was recently

demonstrated that the local expression of IGF-1 is

considerably reduced in skeletal muscle of non-cachec-

tic patients with severe CHF as compared to controls,

even while serum levels of IGF-1, GH, and their binding

proteins remained unchanged [82]. In contrast, IGF-1

receptor expression increases, indicating a possible

feedback mechanism between local IGF-1 concentra-

tions and receptor density.

In a subgroup with low body mass index (\25 kg/m2),

IGF-1 decreased, whereas GH increased significantly,

consistent with the development of a peripheral GH resis-tance [82]. This study also showed that the local expression

of IGF-1 is closely correlated with muscle CSA such that

local IGF-1 deficiency seems likely to increase muscle

atrophy in CHF.

In a related animal study, Schulze et al. [83] demon-

strated reduced local expression of IGF-1 in skeletal

muscle of animals with CHF accompanied by increased

expression of the IGF-1 receptor in the presence of normal

serum levels of IGF-1. Also, significant local expression of

both IL-1b and TNFa were considerably increased in

skeletal muscle [83] and single muscle fiber CSA was

decreased [8385].Overall, these studies suggest that in spite of normal

serum levels of IGF-1 and proinflammatory cytokines,

local expression of IGF-I in skeletal muscle is substan-

tially reduced in CHF. Skeletal muscle changes seem

most likely amidst a local cytokine-based catabolic

process that is a critical aspect of CHF pathophysiology.

Intriguingly, deletion of TNF-a in an animal model of

muscular dystrophy prevents the deterioration of muscle

structure and function [86], suggesting that modifications

to the inflammatory substrate may be a key aspect of

efficient therapeutic manipulations. However, it is

unknown whether this affects local expression and

secretion of anabolic growth factors such as IGF-1.

Effects of inflammation on vasculature

The impact of cytokines and inflammation have also been

studied in respect to vascular architecture and performance.

Experimental evidence suggests that TNF-a impairs the

stability of eNOS mRNA, downregulates eNOS expres-

sion, and may later lead to an increased rate of endothelial-

cell apoptosis [87, 88]. Furthermore, cytokine activity has

been demonstrated to diminish superoxide dismutase [89],

leading to accumulations of free radicals such as super-

oxide anion, which in turn shorten the half-life of NO [90]

and associated propensity for disease instability. Chronic

reductions in peripheral blood flow may increase cytokines

and cytokine activation. Reduced NO exacerbates the

process, with reduced flow as well as reduced cytokine

modifying capacity, in a vicious cycle of disease

escalation.

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Muscle proteolysis and skeletal muscle atrophy in CHF

Muscle mass and strength

Many studies have shown that patients with CHF have

decreased muscle mass and reduced total muscle CSA

compared with healthy normal subjects [9194]. However,

the relationship of these factors with the deteriorations instrength and exercise tolerance observed in patients with

CHF remains controversial. Although overall muscle

strength appears to be decreased in patients with CHF,

most groups have found a preservation of maximal force

per unit area of muscle [92, 95]. Therefore, total muscle

mass appears to affect exercise capacity [39, 94, 96]. Such

findings serve as strong rationale for exercise and adjunct

therapies that might build muscle mass, that is, strength

training.

Theoretically, it is also possible that there are salient

clinical differences that distinguish muscle loss in one

patient from another, that is, skeletal muscle changes maybe very different in cachectic versus non-cachectic

patients. However, these implications have not been clearly

delineated.

Furthermore, even when the lean mass is comparable

between CHF patients and healthy subjects, CHF patients

continue to exhibit an inferior tolerance to exercise [65,

96]. This relative difference is attributable to other aspects

of muscle pathology among CHF patients. Intrinsic dif-

ferences in fiber types, oxidative enzymes, mitochondria,

contractile proteins, and capillary density [33, 40, 42, 62,

97] all contribute to qualitative differences.

Apoptosis

Activation of apoptosis is one mechanism wherein muscle

bulk diminishes with CHF. Apoptosis is tantamount to cell

suicide in which progressive loss of muscle-fiber nuclei

contributes to progressive atrophy. Growth hormone

resistance as well as ambient inflammation (particularly

TNF-a, IL-1, and IL-6 in combination with the transcrip-

tion activator NF-kB) are known catalysts to this

progressive cell loss [98]. Adams showed that apoptosis

was detected in skeletal muscle in 50% of patients with

CHF as compared to no apoptosis in normal healthy con-

trols [69]. Consistently, Vescovo showed oxygen

consumption was negatively correlated with the number of

terminal deoxynuceotidyltransferase-mediated UTP end-

labeling-positive nuclei (a measure of apoptosis) and

skeletal muscle fiber CSA in CHF [99].

Several key signaling patterns appear to regulate apop-

tosis. Inducible NO synthase has been implicated to be both

pro-apoptotic depending on the dosage and timing of its

release. The high iNOS expression present in CHF seems

especially conducive to skeletal muscle apoptosis of skel-

etal myocytes [69, 100, 101].

IGF-1 can modify susceptibility to apoptosis, both with

downregulation of IL-1b-mediated NO formation and fas-

mediated apoptosis [102]. IGF-1 also increases expression

of BCL-2 involving a PI3-kinase/Akt/CREB signaling

cascade [103] that serves to modulate pro-apoptoticstimuli.

Ubiquitin-proteasome-mediated proteolysis

Muscle protein breakdown also results from other cellular

systems. In particular, the ATP-dependent ubiquitin-pro-

teasome system has been implicated as an important

contributor to protein breakdown and skeletal muscle

atrophy in CHF. The role of ubiquitin-proteasome-medi-

ated proteolysis has been well substantiated in other

diseases. Muscle atrophy in diabetes mellitus [104], cancer[105], renal failure [106], starvation [107, 108], sepsis

[109], and CHF [110] has been associated with an

enhanced activation of the ubiquitin-proteasome system.

Specific ubiquitin-conjugating enzymes (E3-ligases)

target proteins for degradation by the proteasome. Two E3-

ligases, atrogin-1 (also called MFbx-1) and MURF-1

(muscle ring finger protein-1), are highly induced in muscle

atrophy of different origin. Gomes et al. reported increased

expression of atrogin-1, a muscle-specific E3-ligase, fol-

lowing starvation [107, 108]. Through a comparable

analysis of genes in atrophying muscle caused by different

mechanisms, Bodine et al. [111] identified the atrogin-1

and MURF-1. Furthermore, animals with targeted deletion

of atrogin-1 or MURF-1 exhibit less muscle atrophy in

response to denervation and hind limb suspension [111].

Schulze et al. [110] demonstrated the key role of ubiq-

uitin-mediated proteolysis for skeletal muscle atrophy in a

CHF animal model as well as the crucial regulatory role of

local IGF-1 in skeletal muscle tissue. Muscle fiber CSA

was significantly reduced 12 weeks after myocardial

infarction and related development of chronic LV dys-

function. Furthermore, increased amounts of ubiquitinated

protein conjugates were demonstrated in extracts from

atrophying skeletal muscle, findings consistent with acti-

vation of the ubiquitin-proteasome pathway in the setting

of chronic LV dysfunction. This analysis demonstrates that

atrogin-1 was strongly induced in several different hind

limb muscles. It also shows that increased IGF-1 sup-

pressed atrogin-1 expression and reduced proteolysis and

atrophy.

Of additional note, infusion of the proinflammatory

cytokine IL-1b induces the expression of atrogin-1 and

TNF-a increases the ubiquitin-conjugating capacity

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myocytes, reinforcing the hypothesis that cytokines con-

stitute key mediators of muscular atrophy [112].

Signaling pathways that link different pathophysiologic

stimuli

Enhanced activation of the PI3K/Akt molecular signalingpathway, downstream from IGF-1, is a key constitutive

step in regulating skeletal muscle atrophy in CHF.

Unchecked, the PI3K/Akt signaling triggers apoptosis, but

Akt phosphorylation inhibits apoptosis as well as the

expression of atrogin-1 and MuRF-1 that otherwise pro-

motes ubiquitin-proteasome-mediated proteolysis [113].

While direct inhibitors of PI3K/Akt phosphorylation have

not been identified in atrophying muscle, such phosphor-

ylation is in fact inhibited during muscle atrophy [114].

Likewise, phosphorylated Akt has been demonstrated in

IGF-1-induced muscle hypertrophy [113, 114]. Phosphor-

ylation of PI3K/Akt also occurs downstream of the b-adrenergic receptor through the second messenger cAMP.

Since expression ofb-adrenergic receptors is suppressed in

CHF, this suggests another vulnerability of CHF patients to

atrophy mediated by the PI3K/Akt pathway, although this

has not been verified in skeletal muscle.

Studies also show that exogenous administration of IGF-

1 regulating growth hormone in a rat CHF model countered

decline in skeletal muscle function, structure, and mor-

phology [115], particularly by phosphorylating Akt to

thereby inhibit FOXO and atrogin-1, that is, IGF-1 stimu-

lates AKT phosphorylation which then moderates

ubiquitin-proteasome-mediated proteolysis.

Foxo transcription factors have also been identified as a

potential mechanism underlying enhanced proteolysis and

muscle atrophy [113, 114]. In mammals, the forkhead tran-

scription factors include Foxo1 (FKHR), Foxo3 (FKHRL1),

and Foxo4 (AFX) [114]. Increased expression of Foxo1

occurs during muscle atrophy [116] but phosphorylation of

Foxo1, 3 and 4 by PI3K/Akt leads to nuclear exclusion

inhibiting their transcriptional activity [113, 114]. IGF-1 also

leads to robust phosphorylation of Foxo4 and mitigates

muscle wasting. Notably, Foxo4 is the most abundant fork-

head transcription factor in skeletal muscle [117].

Gender differences and skeletal muscle in CHF

Men and women CHF patients have been shown to be

different in respect to underlying pathophysiology and

therapeutic responses, especially with respect to skeletal

muscle pathophysiology. However, prior to 1995, few CHF

studies included adequate women for meaningful assess-

ments. Careful review of the literature reveals that of the

studies examining skeletal muscle characteristics in CHF,

fewer than 20% of total subjects have been women.

The Tyni-Lenne group at the Karolinska Institute were

the first to explore skeletal muscle between men and

women CHF patients both at baseline and after 8 months of

knee extensor endurance training [118120]. This series of

investigations showed similar citrate synthase activity

between men and women at both baseline and after train-ing. However, with exercise training, women improved

peak VO2 greater than did men. These analyses also

revealed that female CHF patients had normal type I fiber

distribution but decreased CSA in types I and II compared

to normals. Exercise training with a cycle ergometer cor-

rected the baseline atrophy to within normal ranges.

Duscha et al. [121] reproduced the finding that citrate

synthase was no different between men and women with

CHF and that MHC type I was lower but not statistically

different in CHF versus normal women. This study

extended the field by also showing no difference in capil-

lary density between men and women with CHF. However,when men and women with CHF were compared to normal

controls, the men with CHF had less capillary density

versus healthy men, but the women with CHF had

increased capillary density versus normal women.

In the only other training study that directly compared

skeletal muscle between the genders in CHF, Keteyian

[122] found a robust increase in MHC I in men and a

concordant increase in peak VO2. However, women with

CHF had no training effects, that is, an outcome that was

discordant with Tyni-Lenne, who found that with training,

women had a relatively greater improvement in oxygen

consumption.

Overall, this limited body of literature comparing

peripheral manifestations of CHF in men and women

suggests that women with CHF have slightly more oxida-

tive capacity in their skeletal muscle than do men with

CHF, possibly indicating that CHF produces less impact on

skeletal muscle in women than in men. However, the

potential for skeletal muscle to favorably adapt to exercise

training, and its relation to improved functional capacity in

the context of gender differences, remains a keen topic of

research interest.

Overview of exercise training studies

While this review remains focused on peripheral aspects of

CHF, and corresponding peripheral benefits of exercise,

benefits of exercise on central cardiac function are also

relevant. As detailed by other authors elsewhere in this

issue, cardiac output may improve with exercise training,

increasing blood supply to support skeletal muscle work

demands.

30 Heart Fail Rev (2008) 13:2137

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Although a number of small exercise training studies

have examined the adaptations of skeletal muscle to

exercise training, these studies have been difficult to

interpret for a variety of reasons. To date, there has been no

large (highest number of any one study is 16 CHF patients)

randomized control study adequately powered and

designed to detect changes across multiple markers of

oxidative capacity in skeletal muscle. This gap in the lit-erature is especially appreciated when one considers that

the ability to detect and relate physiologic differences

before and after an intervention is difficult even with robust

subject numbers and large changes. Furthermore, CHF has

a continuum of functional classifications, making it diffi-

cult to differentiate how severity of disease impacts

skeletal muscle adaptability within each category. Few

studies have compared men versus women. Last, the dose

of exercise (training range and duration) and mode (cycle,

walking, knee-extensor) is all slightly different between

studies. For these reasons there have been a number of

inconsistencies, conflicting data, and null findings.

Effects of aerobic exercise training on intrinsic skeletal

muscle properties

Table 1 summarizes the 17 studies we found that included

both an aerobic exercise intervention and skeletal muscle

biopsies before and after exercise training. This table pri-

marily highlights intrinsic oxidative characteristics.

Despite heterogeneous designs and methods, some con-

sistent findings do emerge; in particular, studies show that

exercise training increases oxidative enzyme activity in

CHF patients. Changes in mitochondria structure correlated

with improvements in peak VO2 and lactate threshold [123,

124]. Other studies demonstrate increases in citrate syn-

thase (2545%) [48, 118, 125127]. Furthermore, increases

in mitochondrial enzymes have been correlated to mito-

chondrial structure and function [25].

Nonetheless, data pertaining to fiber types before and

after exercise training have been much more ambiguous.

Of the 17 aerobic exercise studies assessed, only 7 mea-

sured changes in fiber type or MHC, and of these, 5 out of 7

demonstrated no change and only 2 of the 7 show increased

type I fibers. Furthermore, in one of the two studies that

indicated an elevation in type I fibers, it was only a modest

4% increase. Some studies show shifts from IIb to IIa fiber

type but, in general, the plasticity of fiber shifting as a

result of exercise training was underwhelming. Overall,

these data indicate that fiber type does not shift readily

toward more oxidative forms with exercise training. Sim-

ilarly, data pertaining to capillary density before and after

exercise training have not shown obvious differences. Of

the 17 trials assessed, only 5 included capillary density

responses to exercise training. Three showed increased

capillary density and two did not (Table 1).

It may be concluded that improvements in aerobic

capacity do not necessarily elicit or result from increases in

aerobic fiber types. Therefore, the fundamental decreases

in oxidative fibers that occur with CHF (compared to

healthy controls) are not completely reversible with exer-

cise training. Furthermore, improved oxidative capacity ismore likely linked to oxygen utilization that is determined

by changes in intrinsic properties of skeletal muscle.

Exercise as a means to modify ambient tissue

inflammation

A broader benefit of exercise training relates to its potential

to modify underlying tissue inflammation that otherwise

deranges muscle function, and which also underlies

impaired NO stimulation and efficacy, as well as proclivity

to muscle atrophy. Gielen et al. [126] showed benefits ofaerobic training to reduce TNF-a, IL-1B, IL-6, and iNOS in

skeletal muscle of CHF patients. Importantly, these effects

in skeletal muscle were independent of serum levels.

Accumulating evidence suggests that exercise

enhancements to endothelial function may promote these

anti-inflammatory benefits. Physical training has been

shown to improve cardiac output during exercise with

related increases in endothelial shear stress and associated

NO stimulation. Not only does NO decrease peripheral

resistance in working muscle, with favorable redistribution

of blood flow [24, 128], but it also induces anti-inflam-

matory effects. Diminished free radicals and inflammatory

cytokines (i.e., TNF-a) have been demonstrated [129, 130].

While increases in NO bioactivity may dissipate within

weeks of training cessation, studies of healthy subjects

indicate that if exercise is maintained, the short-term

functional adaptation catalyzes NO-dependent structural

changes, leading to more enduring arterial remodeling and

structural normalization of the endothelium [131]. Simi-

larly, as exercise achieves favorable anti-inflammatory

benefits in the skeletal muscle, the implications are broad.

Secondary molecular signaling effects are likely, favorably

affecting skeletal muscle molecular signaling patterns that

otherwise result in atrophy and metabolic declines.

Effects of exercise on underlying molecular signaling

pathways

IGF-1 and exercise

Muscular stretch is a potent stimulator of IGF-1. McKoy

et al. [132] reported that 4 days of muscle stretch

Heart Fail Rev (2008) 13:2137 31

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significantly induced IGF-mRNA starting as early as 12 h

after the stimulus. Exercise training as a natural form of

stretch exposure has similar effects on skeletal muscle IGF-

1 expression. In a model of treadmill exercise in young

rats, Eliakim et al. [133] described a significant increase in

skeletal muscle IGF-1 protein levels after 6 days with no

change in systemic IGF-1 serum concentrations. Similarly,

a greater than a two times increase in local IGF-1 expres-sion after 6 months of exercise training was found in

patients with stable CHF [134, 135].

In two other studies involving non-CHF populations,

one showed increased IGF-1 immunoreactive cells in

skeletal muscle biopsies obtained after 1 week of terrain

marching [136]. The second showed a six times increase in

local IGF-1 expression after a combined intervention of

nutritional supplementation and resistance training [137].

Therefore, the local IGF-I-deficiency responds to long-term

exercise, indicating that the catabolic state in the skeletal

muscle of CHF patients is at least partially reversible by

adequate rehabilitation [134]. Furthermore, Singhs studyraises consideration of resistance training as potentially a

more potent and efficient means to achieve changes in

growth peptides and anti-inflammatory benefits.

Rationale for different training modalities

The preponderance of exercise training studies for CHF

have utilized aerobic training modalities; however, many

now look to strength training as a synergistic exercise

modality. Whereas rationale for aerobic training in cardiac

patients was originally premised on expectations for

improved inotropic and chronotropic capacities, outcomes

have mostly demonstrated clinical improvements after

exercise training that are attributable to augmented skeletal

muscle oxidative metabolism. Many hypothesize that

resistance training may more efficiently induce skeletal

muscle molecular signaling patterns that achieve clinical

benefits. Notably, resistance training is the exercise

modality that has the most potential to increase muscle

mass, suggesting it may more successfully respond to the

muscle loss and weakening of CHF. In an animal study,

Baldwin [138] describes differences in how specific exer-

cise modalities impact muscle plasticity. This study shows

myosin heavy chain gene expression is regulated by

mechanical stimuli and transcriptional events vary

depending on the exercise utilized.

Despite the promise of resistance training in CHF, there

is some controversy concerning its effect on peak VO2.

While some studies have shown an increase in peak VO2following weight training [139141], others have failed to

reproduce these findings in either CAD [142] or CHF [143]

populations. Many report that resistance training improves

other clinical measures such as sub-maximal ventilation and

lactate threshold as well as total exercise time [66, 141,

143]. A related analysis by Williams [141] showed that

increased mitochondrial ATP production was significantly

related to improvements in peak VO2. This finding suggests

that resistance training can have beneficial effects similar to

that of aerobic training on the skeletal muscle of CHF.

In other analyses, multiple investigators assert rationale forexercise regimens that combine aerobic and strength training

as an approach that is particularly likely to enhance function.

Maiorana et al. [144] showed 18.4% improved exercise time

and 13.4% improved peak VO2 after a 12-week aerobic plus

circuit weight-training program in CHF patients. Delagardelle

et al. [145] and Selig [146] also showed significant increases

in peak VO2 using a combination of resistance and aerobic

training. Furthermore, Delagardelle [147] demonstrated that a

combined program of endurance and strength training was

superior to a program of endurance training alone for the

improvement of peak VO2.

Investigators have begun to analyze skeletal musclehistology and biochemistry as a result of resistance train-

ing. Pu et al. [66] showed increased muscle fiber area

(9.5% for type 1 and 13.6% for type II muscle fibers) as

well as improved oxidative capacity (35% increase citrate

synthase activity). Magnusson [125] showed 9% increased

CSA of the quadriceps femoris muscle.

Related analyses are only beginning to focus on the

underlying biochemistry, histology [148], and associated

muscle signaling cascades. Specific benefits of resistance

training on IGF-1, myostatin, and several other key medi-

ators are pathways and dynamic areas of investigation

pertinent to heart failure as well as to aging and other

chronic disease states that are associated with muscle loss

and weakening [149, 150].

As these investigations evolve, many related issues

regarding the interplay between skeletal muscle and sus-

taining blood supply need to be explored. While studies

demonstrate that resistance training improves skeletal

muscle histology, biochemistry, and muscle mass, it

remains unknown if there is adequate cardiac output to

employ and sustain these added benefits. In summary,

further research is necessary to evaluate the value of

resistance training in CHF. Future challenges include

optimizing exercise prescription without compromising LV

function as warned by the American Heart Associations

position stand on resistance exercise training in individuals

with cardiovascular disease [151].

Conclusion

As insights regarding heart failure have evolved, the

overall complexity of disease has become more evident.

32 Heart Fail Rev (2008) 13:2137

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Consistently, it has become clear that peripheral mecha-

nisms of disease, particularly those pertaining to tissue

perfusion and skeletal muscle oxidative metabolism, gen-

erate key impact on disease progression, and also create

potential for novel therapeutic interventions. Certainly,

exercise training has been demonstrated to improve many

of the vascular and skeletal muscle features that have been

associated with CHF. Ongoing research points to thecomplex interplay between vascular and skeletal muscle

performance as the search continues for optimal thera-

peutic strategies. Eventually, it seems likely that specific

types of exercise, possibly a combination of aerobic and

resistance modalities, will be identified that target specific

peripheral endpoints and how they impact functional

outcomes.

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