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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
e-mail: [email protected]
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
e-mail: [email protected]
D. E. Forman (&)
Brigham and Womens Hospital, 75 Francis Street, Boston, MA
02115, USA
e-mail: [email protected]
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
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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.
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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
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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.
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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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