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MUSCLE OXYGEN TRANSPORT AND UTILIZATON IN HEART FAILURE:1
IMPLICATIONS FOR EXERCISE (IN)TOLERANCE2
3
David C. Poole, Daniel M. Hirai, Steven W. Copp,4
and Timothy I. Musch5
6
Departments of Anatomy, Physiology & Kinesiology,7
Kansas State University, Manhattan, KS 66506-58028
9
10
11
12
13
14
15
16
17
David C. Poole18Department of Anatomy and Physiology19
College of Veterinary Medicine20
Kansas State University21
Manhattan, KS 66506-580222
Articles in PresS. Am J Physiol Heart Circ Physiol (November 18, 2011). doi:10.1152/ajpheart.00943.2011
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25
26
Abstract27
The defining characteristic of chronic heart failure (CHF) is an exercise intolerance that is linked28
inextricably to structural and functional aberrations in the oxygen (O2) transport pathway. CHF reduces29
muscle O2 supply whilst simultaneously increasing O2 demands. CHF severity varies from moderate to30
severe and is assessed commonly in terms of the maximum oxygen uptake (VO2max, which relates31
closely to patient morbidity and mortality in CHF and forms the basis for Weber and colleagues32
classifications of heart failure, 167), speed of the VO2 kinetics following exercise onset and during33
recovery and the capacity to perform submaximal exercise. As the heart fails cardiovascular regulation34
shifts from controlling cardiac output as a means for supplying the oxidative energetic needs of35
exercising skeletal muscle and other organs to preventing catastrophic swings in blood pressure. This36
shift is mediated by a complex array of events that includes altered reflex and humoral control of the37
circulation, required to prevent the skeletal muscle sleeping giant from outstripping the38
pathologically-limited cardiac output (Q
TOT), and secondarily impacts lung (and respiratory muscle),39
vascular and locomotory muscle function. Recently, interest has also focused on dysregulation of40
inflammatory mediators including tumor necrosis factor (TNF) and interleukin 1 (IL-1) as well as41
reactive oxygen species (ROS) as mediators of systemic and muscle dysfunction. This brief review42
focuses on skeletal muscle to address the mechanistic bases for the reducedVO2max, slowed VO243
kinetics and exercise intolerance in CHF. Experimental evidence in humans and animal models of CHF44
unveils the microvascular cause(s) and consequences of the O2 supply (decreased)-O2 demand45
(increased) imbalance emblematic of CHF. Therapeutic strategies to improve muscle microvascular and46
oxidative function (e.g., exercise training and anti-inflammatory, antioxidant strategies, in particular)47
and hence patient exercise tolerance and quality of life are presented within their appropriate context48
of the O2 transport pathway.49
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52
Chronic Heart Failure A Perfect Storm of Multiple Organ System Dysfunction53
As the heart fails, following a myocardial infarction or other etiology,Q
TOT at rest, and particularly during54
muscular exercise, is reduced consequent to a diminished ejection fraction, stroke volume and a heart55
rate response that is insufficient to compensate for the reduced stroke volume. This is the initiating56
condition for a cascade of events that affects multiple organ systems (Figure 1, rev. 129,130). There is a57
global sympathetically-mediated vasoconstriction, that serves initially to maintainQ
TOT at pre-pathology58
levels and which subsequently impairs the ability to distribute and redistribute Q
TOT to and within59
skeletal muscle(s) (Q
m, 120,124,160,173). Enhanced humoral mediators including altered circulating60
angiotensin, norepinephrine, endothelin-1 (154) and vasopressin levels also contribute to the systemic61
vasoconstriction in CHF and intravascular sodium and water retention act to further impair vasodilation62
(177) as do a plethora of events within the peripheral vasculature (vide infra, 25,44,45;rev. 129,130). In63
addition, Group III (mechanosensitive) and IV (metabosensitive) afferents within the contracting muscles64
increase global sympathoexcitation (9,35, rev. 164). In support of Coats et al.s muscle hypothesis (31)65
for CHF Wang et al. (164) have demonstrated that CHF sensitizes Group III afferents which likely66
contributes to the exaggerated exercise pressor response (EPR). Despite the same studies67
demonstrating that Group IV afferents are desensitized in CHF it is pertinent that the far slowerVO268
kinetics, lower VO2 and microvascular PO2 (Figures 2-6) will all exacerbate production and accumulation69
of metabolites that ultimately stimulate these afferents. Thus, despite their relative desensitization the70
role of the Group IV afferents in the EPR is likely substantial in CHF. This eventuality would certainly help71
explain how exercise training-induced speeding of the VO2 kinetics (131,139) reduces or even prevents72
a greater EPR in CHF (165).73
74
At the proximal end of the O2 transport pathway in the lung, CHF patients develop pulmonary75
dysfunction including ventilation-perfusion (V
A/Q
) mismatch accompanied by reduced O2 diffusing76
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diaphragm and other respiratory muscles can stealQ
from the locomotory muscles (79). In CHF this82
effect is accentuated (122,126) redistributing moreQ
TOT towards the respiratory muscles and, by83heightening sympathetic vasoconstriction of locomotory muscles, further impoverishing theirQ
m and84
O2 supply and compromising exercise tolerance. This condition may be exacerbated further if CHF is85
accompanied by anemia secondary to dysfunctional iron metabolism and heightened inflammatory86
stress (103). Furthermore, within skeletal muscles in CHF the capacity to utilize O2 is impaired with87
reductions in mitochondrial oxidative enzyme activity and volume density as well as mitochondrial88
dysfunction (e.g., 41,58,65,78,153). It is pertinent that, although skeletal muscle capillarity may (e.g.,89
171) or may not (58) be reduced significantly, across control and CHF populations the number of90
capillaries per fiber correlates highly with mitochondrial volume density (58). In addition, CHF increases91
the proportion of capillaries that do not support red blood cell (RBC) flux at rest and during contractions92
(137).93
Impact on Exercise Responses94
Four key parameters of aerobic function are the maximal VO2 (VO2max), VO2 kinetics, VO2 gain (e.g.,95
ml O2/watt/min for cycling, an approximate measure of efficiency), and the lactate (Tlac) or gas96
exchange (GET) threshold (131,133-135,139,168,169). These parameters define the gas exchange (i.e.,97
V
O2) response to exercise in the transient (i.e., following exercise onset, non-steady state) and steady98
state conditions, and, as such, link tightly with exercise tolerance or impediment thereof.99
VO2max100
VO2max has historically been considered the sentinel parameter of integrated cardiovascular function101
and has been used widely to judge the severity of CHF (52,71,98,109,111,167,168). Specifically, Class A,102
VO2max > 20 ml/kg/min, Class B, 16-20, Class C, 10-15, Class D,
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exercise (137) all increasing VO2max or muscle specific VO2max), pulmonary and muscle diffusive O2110
capacities also contribute importantly toV
O2max. Moreover, at altitude, after exercise training and in111
extremely fit individuals (high VO2max) the relative importance among O2 perfusive and diffusive112
capacities with respect to determining VO2max may shift. In CHF it was traditionally thought that113
VO2max was reduced solely consequent to the loweredQ
TOT and resultantQ
m (perfusive O2 transport)114
which was supported by the low venous O2 contents measured either centrally (pulmonary artery) (167)115
or in the exercising muscle(s) effluent venous blood (88). Specifically, the ability to reduce venous O2116
content and increase fractional O2 extraction (arterial-venous O2 difference) to a similar (or better)117
extent as seen in healthy subjects led to the presumption that the effective muscle O2 diffusing capacity118
(DO2m) was unimpaired. However, as can be seen from Figure 2, the Fick principle:119
VO2 = Q
m x (arterial - venous O2 content)120
and Ficks law of diffusion:121
VO2 = DO2m x (microvascular PO2 intramyocyte PO2)122
conflate to yield VO2max where the curved lines represent perfusive O2 transport (Q
O2m = Q
m x123
arterial O2 content) and the straight lines from the origin represent DO2m. Therefore, venous O2 content124
(or microvascular PO2 (PmvO2) as shown) in CHF can either be normal or lowered at VO2max even in the125
presence of a substantially decreased DO2m. This effect is seen for large muscle mass exercise (e.g.,126
conventional cycling) and small muscle mass exercise (i.e., knee extension) (58). The precise127
microvascular mechanisms for the reduced DO2m in CHF involve impaired capillary hemodynamics at128
rest and during contractions and are considered in detail below (seeSkeletal Muscle Blood Flow,129
Capillary Hemodynamics and Microvascular PO2). What should be appreciated from Figure 2 is that, with130
respect to fractional O2 extraction and thus PmvO2 and venous PO2, there is an interdependence131
between the muscle perfusive (Q
O2m) and diffusive (DO2m) relationships that may be expressed as132
(138):133
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normal (ratio DO2m/Q
m) or, as shown in Figure 2, increased (ratio DO2/Q
m). The importance138
of the reduced DO2m in CHF is evident when vasodilator treatment increasesQ
O2m but not V
O2max139(47,48). To maximize their beneficial effect on VO2max therapeutic interventions should effectively140
increase both perfusive (Q
O2m) and diffusive (DO2m) O2 transport.141
VO2 Kinetics142
Healthy individuals, let alone CHF patients, rarely exercise at V
O2max yet daily activities require myriad143
increases (and decreases) in metabolic rate and hence VO2. The speed of these adjustments define144
ones VO2 kinetics in terms of the overall time constant (, time to reach 63%) of the response which145
may be 20-30 s in young healthy individuals but slowed to several minutes in CHF patients (Figure 3,146
81,118,147,148). Importantly, the speed of the VO2 kinetics has been considered to have even better147
prognostic value in CHF than V
O2max (on-kinetics, 142; off-kinetics, 125). Both the close-to-148
instantaneous Phase I (driven predominantly by increased pulmonary blood flow, omitted from Figure 3149
for clarity) and the subsequent primary (Phase II) response, thought to reflect the muscle VO2 kinetics150
(72), are impacted by CHF (148) reflecting a failure to both increaseQ
TOT and muscle VO2. The151
importance of this slowed VO2 kinetics is that the steady state O2 requirement for a given task will152
almost certainly be no lower (and may even be higher, see below) in CHF and so, for any given metabolic153
transition, the CHF patient will incur a greater O2 deficit and therefore more extreme intracellular154
perturbation of high energy phosphagens and acid-base (Figure 3). Importantly, the greater substrate-155
level phosphorylation associated with slower VO2 kinetics accelerates glycogenolysis and contributes to156
fatigue and the ensuing exercise intolerance (123,131,139). For a given metabolic transition (VO2) the157
O2 deficit incurred may be estimated as: V
O2. Thus, for the same metabolic transition of, for example,158
1 l O2 the healthy individual with fast kinetics ( = 30 s or 0.5 min) will incur an O2 deficit of 0.5 l O2159
(0.5x1.0) whereas for the CHF patient with slowed kinetics ( = 120 s or 2 min) their deficit will be 2 l O2160
(2.0x1.0) and consequently a muscle biopsy of the patients working muscles would reveal lower [PCr]161
+
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supply dependency (O2 delivery dependent zone, Figure 3). The direct consequences of this slowed VO2167
kinetics in CHF and other diseases/conditions are a greater psychological perception of effort, greater168
intracellular perturbation of phosphagens, acid-base and glycogen and a related decrease in exercise169
tolerance (see Figure 13 of ref. 139).170
VO2 Gain and the Slow Component ofVO2 Kinetics171
For exercise above the lactate threshold (>Tlac i.e., in the heavy or severe intensity domains) an172
additional VO2 cost (or slow component) becomes evident beyond the faster primary (Phase II) kinetics173
as VO2 rises considerably above the ~10 ml O2/watt/min gain characteristic of moderate (
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Skeletal Muscle Blood Flow, Capillary Hemodynamics and Microvascular PO2 (PmvO2)196
Healthy197
In health with normal arterial O2 content (~20 ml O2/100 ml), Q
TOT andQ
m increase between 5 and 6 l198
per lVO2 (rev. 60). Following the onset of muscular exercise theQ
TOT increase is extremely rapid owing199
to an essentially instant vagal withdrawal accelerating heart rate (Phase I) with a subsequent increase in200
stroke volume and further elevation of heart rate (Phase II) drivingQ
TOT andQ
m kinetics that are201
appreciably faster than their VO2 counterparts (40,95,133,157,172). This profile supports the O2202
delivery independence ofVO2 kinetics in healthy young individuals (Figure 3, refs. 133,139). Thus,Q
m203
may increase sufficiently fast for moderate (72) as well as heavy and severe exercise (13,96) such that204
increasedQ
O2m exceeds muscle VO2 and consequently effluent venous O2 content increases205
transiently as fractional O2 extraction is decreased. There is evidence that both rapid arteriolar206
vasodilation (19, rev. 28) and muscle pumping action (rev. 157) contribute to this almost instantaneous207
(within 1 s) increase in muscle (95,157) and capillary (92) Q
.208
Across muscles of different fiber type composition the proportionality of the increase inQ
m to VO2 is209
similar but fast twitch muscles have a lower Q
m at rest such that PmvO2 is lower (and fractional O2210
extraction higher) at rest and low metabolic rates than for slow twitch muscles (23,60,117). These fast211
twitch muscles may have a slower rate ofQ
m increase following the onset of contractions and be forced212
to rely more heavily on O2 extraction than slow twitch muscles (23,117). Importantly, as most skeletal213
muscle capillaries may support red blood cell (RBC) flux at rest the increasedQ
m with contractions214
represents augmented RBC flux (and velocity) within already flowing capillaries (92,132). Thus, following215
the onset of contractions increased blood-muscle O2 flux (diffusional O2 capacity, DO2m) occurs via a216
combination of (132): 1. Increased RBC flux and velocity in individual capillaries. 2. Recruitment of217
additional capillary exchange surface by elevating capillary hematocrit and the length of capillary over218
which O2 flux occurs (i.e., longitudinal recruitment). 3. Reduction of intramyocyte PO2 to establish a219
sufficient capillary-mitochondrial O2 gradient. 4. Myoglobin deoxygenation to enhance intramyocyte O2220
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elevation ofQ
m (Phase II, 108,174-177). For a share of this reducedQ
O2 exercising skeletal muscle225
must overcome exaggerated sympathetic, humoral and reflex-mediated vasoconstriction to compete226
with elevated energetic (andQ
m) demands of the respiratory muscles (122,126) and an altered227
distribution of available Q
TOT among active locomotory muscles based, in part, upon their fiber type228
composition (i.e., greaterQ
m to low oxidative Type II and lowerQ
m to Type I/oxidative Type II muscles229
and muscle fibers in CHF versus healthy animals, 51,124). At VO2max the reducedQ
TOT (and any230
decreased arterial [O2]) lowersQ
O2mwhereas subsequent redistribution of that loweredQ
TOT away231
from the major locomotory muscles provides an additional constraint on QO2m (122,126, Figure 2).232
Compounding theseQ
TOT distributional problems, arterioles within the active muscles themselves have233
an inherently greater vasoconstrictor tone (44,45)234
At the muscle capillary level CHF promotes capillary involution (171) and reduces the percentage of235
capillaries that support RBC flux at rest and during contractions (136). Crucially, those capillaries that do236not flow at rest remain stagnant during contractions and this helps place a low limit on DO2m (see237
Figure 2) as it lowers the number of oxygenated RBCs in the capillary bed at a given moment and238
therefore available to contribute to the instantaneous blood-myocyte O2 flux. Figure 5 (top)239
demonstrates that, even in those capillaries that do support RBC flux at rest, the response to240
contractions is extremely sluggish. Consequently, even though mitochondrialVO2 kinetics may be241
impaired in CHF (and especially severe CHF, 41),Q
O2m kinetics are more affected and the Q
O2m/VO2242
ratio falls much lower driving PmvO2, either transiently (moderate CHF in young animals, Figure 5243
(bottom), 46) or during the steady-state (severe CHF, old animals, 21 cf. 18,22), to extremely low values.244
Importantly, muscles comprised predominantly of slow twitch fibers are impacted most drastically (20).245
Thus, compared with healthy muscles, in CHF the PmvO2 (driving blood-myocyte O2 flux) is lowered at246
that time when muscleVO2 is, or should be, increasing most rapidly with the result that VO2 kinetics247
become O2 delivery (i.e.,Q
O2m) limited and very slow (Figure 3). This response is akin to the248
overshoot of the muscle hemoglobin+myoglobin deoxygenation profile measured by near-infrared249
spectroscopy by Sperandio and colleagues (150) in CHF patients. In an attempt to preserve the blood-250
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earlier or faster following cessation of muscle contractions in CHF keeps PmvO2 low, reduces255
intramyocyte PO2 and retards VO2 and PCr recovery kinetics (89,90). It is pertinent that recoveryVO2256
kinetics can often be determined with greater fidelity and reproducibility than its counterpart at the257
beginning of exercise (89,90). Thus, altered off-transient VO2 kinetics, sometimes in the presence of258
indiscernibly different on-kinetics, may identify O2 transport/utilization derangements in CHF patients259
(147) and therefore correspond more closely with the extent of functional compromise (39,90,125).260
This effect has also been demonstrated for the dynamics of muscle PmvO2 as seen in Figure 6(left261
panel) for severe CHF (33). Notice the lowered PmvO2 at rest and during contractions in CHF and the262
PmvO2 undershoot present in the response. However, the most pronounced difference in the kinetics263
of the PmvO2 response is evident in the off-transient (i.e., recovery) where the control muscle recovers264
to baseline well before its CHF counterpart has reached 50% recovery. It is pertinent that Copp et al.265
(33) demonstrated a strong correlation (Figure 6, right panel; r = 0.76, P
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Mechanisms Limiting Increases of Muscle Blood Flow (Q
m) in CHF285
Almost every aspect ofQ
m control is disturbed in CHF as seen in Figure 7. Vasoconstriction is enhanced286
by sympathetic nervous system-mediated -adrenergic tone (consequent to enhanced peripheral287
chemoreceptor sensitivity and heightened metaboreflexes) and increased circulating catecholamines,288
angiotensin II, arginine vasopressin and endothelin-1 (25,154 rev. 129,130). The efficacy of the muscle289
pump is impeded by elevated post-capillary resistance (115,146,174,175) and increased vascular290
stiffness. Endothelial function is compromised by endothelial cell damage and impaired repairability, in291
part, due to low circulating endothelial progenitor cells (CPCs, 54). Nitric oxide (NO) bioavailability is292
compromised which presumably constrains sympatholysis (the ability to oppose -adrenergic293
vasoconstriction, 155) and shear stress-mediated vasodilation. In turn, inadequateQ
m andQ
O2m will294
promote hypoxic vasodilation and increase vasodilatory metabolite efflux from the contracting295
muscle(s) (lactate, H+, adenosine, inorganic phosphate, potassium). The eventual outcome (i.e., reduced296
Qm and particularly PmvO2) in CHF indicates that the net balance favors reduced vascular perfusion and297
impairedQ
O2m.298
Within muscle and other tissues CHF increases TNF and IL-1 levels and the anti-inflammatory299
interleukin 10 (IL-10) may decrease (14,54) irrespective of whether circulating concentrations are300
altered. There is also an aggravated oxidant-antioxidant imbalance. All of these changes can impact NO301
bioavailability and, given the importance of decreased NO bioavailability in muscle and exercise302
dysfunction in CHF (see Role of NO in Regulating Contracting MuscleQ
O2/VO2 Matching below), have303
been the subject of significant attention.304
305
Role of NO in Regulating Contracting MuscleQ
O2/VO
2Matching306
NO bioavailability can exert a commanding role in the matching ofQ
O2m to VO2in contracting rat307
muscle. For example, Hirai and colleagues (82) have determined in rats that NO-mediated vasodilation308
helps regulate the distribution ofQ
O2m among active muscle fibers based upon their oxidative capacity.309
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nitroprusside (an NO source) restores the PmvO2 profile from that present in moderate CHF back to that315
seen in the healthy animals (59). However, it must be acknowledged that elevating intracellar [NO] has316
the potential to decrease mitochondrial VO2 (10,11,100) and hence restore the healthyQ
O2m/VO2317
ratio by decreasing the denominator as well as increasing the numerator. Notwithstanding this concern,318
it is evident that increased NO bioavailability has the potential to enhance blood-myocyte O2 flux in CHF319
by restoring PmvO2. This potential for compromised NO bioavailability to explain PmvO2 (and thus320
functional) derangements in CHF highlights the importance of resolving the mechanisms responsible for321
the reduction in NO bioavailability in CHF and developing/optimizing therapeutic strategies for322
mitigating this effect (Figure 7, inset (bottom right panel)).323
Inflammatory Mediators reduce NO Bioavailability in CHF324
CHF-induced muscle vascular dysfunction and the associated decreased NO bioavailability is mediated,325
in part, by a combination of the reduction in endothelial cell tetrahydrobiopterin (BH4, an essential326
cofactor for NOS), superoxide dismutase (SOD), catalase and glutathione peroxidase (GPX) protein327
expression and activity as well as increased NADPH oxidase protein expression and activity each of328
which serves to elevate superoxide radicals (O2-) and decrease NO (Figure 7, inset (bottom right panel),329
17,42,82,93,97,106,110). Inflammatory mediators TNF and IL-1 promote oxidative stress and have330
been heavily implicated in this process (1,2,24,34,53,65,67,105,156,158). Reducing BH4 uncouples331
endothelial NOS (eNOS) lowering NO production (110,149) and generating O2- which itself enhances NO332
degradation and produces the peroxynitrite ROS (Figure 7, inset (bottom right panel), 149). Moreover,333
enhanced O2- will, by the action of SOD, elevate hydrogen peroxide (H2O2) which, although a vasodilator334
in its own right, in the presence of Fe2+ yields the potent vasoconstrictor OH - (hydroxyl radical) via the335
Fenton reaction. In addition, elevated cytokines (TNF, IL-1) promote iNOS induction such that336
intracellular [NO] rises and inhibits key oxidative enzymes and mitochondrial creatine kinase (4,65,76) as337
well as promoting apoptosis (3).338
In aged rats increased BH4, induced via acute exogenous bolus sepiapterin (substrate for BH4 synthesis)339
t t t i t i i i NO i li i k l t l l t i l d t fl340
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ischemic conditions (in this respect analogous to CHF, 38,50,145) and has demonstrated clinical efficacy345
in CHF patients (12,145). Pentoxifylline may also help restore more normal skeletal muscle346
hemodynamics in CHF by reducing the CHF-enhanced sympathoexcitation via central effects within the347
paraventricular nucleus and elsewhere (75). However, this remains to be empirically determined.348
349
Specific Effects of CHF and Exercise training on Mediators of NO Bioavailability350
In contrast to CHF, NO bioavailability and endothelial function in skeletal muscle and heart are351
upregulated by exercise training (73,101,114,144) particularly against a background of CHF (Figure 8,352
34,161). The effect of exercise training and its ability to combat the predations of CHF has been353
attributed, in part, to increased BH4 (16,106), as well as decreased oxidative stress (increased SOD,354
catalase and GPX, 62,68,102,106,140), reduced TNF and IL-1 (1,32,66,104) and reduced iNOS which355
decreases intramyocyte [NO] and presumably lessens its pernicious intracellular consequences (65).356
Moreover, exercise training may increase muscle capillarity (facilitated by preservation of the vascular357
endothelial growth factor (VEGF) signaling pathway in CHF patients, 57) and oxidative function in CHF358
patients (56) as it does in healthy individuals (26,141) as well as restore levels of the anti-inflammatory359
mediator IL-10 (14). In addition, exercise training may improve vascular endothelial function via a c-Src-360
dependent increase of eNOS expression and NO bioavailability as well as help restore endothelial repair361
and function by elevating CPCs (37,54,56,62,97,101,114).362
363
Conclusions364
CHF compromises almost every facet of the O2 transport pathway which can explain much of the365
exercise intolerance and premature fatigue in this condition. VO2max is decreased by impaired366
perfusive O2 transport to and within the active muscles and also compromised diffusional O2 transport367
that may result from failure to sustain RBC flux within a substantial proportion of the capillary bed368
creating a marked temporal and spatial imbalance between O delivery (Q
O m) and requirements369
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for tasks or activities which constitute moderate exercise (
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Sydney, provides evidence that, beyond the failing heart, the O2 transport predations of CHF are405
potentially reversible.406
407
Acknowledgments408
This work was supported, in part, by grants from the National Institutes of Health (HL-50306, AG-19228,409
HL-108328), the American Heart Association (Grants-in-Aid to D.C.P., T.I.M.), CapesBrazil Fulbright410
Fellowship program (to D.M.H.).411
412
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413
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983
984
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985
Figure Legends986
Figure 1. Predations of chronic heart failure (CHF) on the O2 transport pathway. Although a987
dysfunctional heart and impaired ability to generate cardiac output are the core events CHF is a multi-988
organ disease affecting all steps in the O2 transport pathway. CHF-induced lung dysfunction989
redistributes blood flow (Q
) to the respiratory muscles via locomotory muscle vasoconstriction, there990
may be systemic anemia, systemic vasoconstriction and elevated left ventricular end diastolic pressures991
as well as a plethora of structural and functional adaptations (increased vasoconstriction, impaired992
vasodilation and muscle pump) that compromise skeletal muscle perfusional and diffusional O2993
transport. See text for more details.994
Figure 2. Facets of the exercise response in chronic heart failure (CHF) I: VO2max. Schematic illustrating995
how the perfusive (curved lines, Fick principle, VO2 = Q
m (arterial-venous O2 content)) and diffusive O2996
(straight lines from origin, Ficks law, VO2 = DO2m (PmvO2 PintracellularO2)) transport conflate to yield997
theV
O2max during large muscle mass exercise (e.g., cycling). Note that, in CHF (dashed lines),V
O2max is998reduced by both impaired perfusive and diffusive O2 transport and that PmvO2 may either be the same999
or lower (arrows on abscissa) than found in health even in the presence of marked diffusional1000
derangements. Mechanisms responsible for these perfusive and diffusive O2 transport derangements1001
include: reduced bulk blood flow and O2 delivery, impaired blood flow distribution, reduced capillarity1002
and percentage of capillaries supporting red blood cell (RBC) flux, lowered functional capillary1003
hematocrit (#RBCs adjacent to contracting myocytes in flowing capillaries) and impaired mitochondrial1004
function. See text for additional details.1005
Figure 3. Facets of the exercise response in chronic heart failure (CHF) II: VO2 kinetics. CHF slows VO21006
kinetics (increased time constant, ) in response to moderate (as shown), heavy and severe intensity1007
exercise, in part, by lowering muscle perfusive and diffusive O2 transport such that O2 delivery becomes1008
limiting (top panel, see grey O2 delivery dependent zone). Note that these slowedVO2 kinetics will1009
mandate a greater O2 deficit leading to greater intracellular perturbations that accelerate glycogen1010
depletion and sow the seeds for exercise intolerance. Mechanisms responsible for slowedV
O2 kinetics1011in CHF include: slowed/absent arteriolar vasodilation, impaired muscle pump (venous congestion),1012
slowed capillary hemodynamics, lowered microvascular PO2, impaired mitochondrial function, greater1013
intracellular perturbation (as detailed in bottom panel). See text for additional details.1014
Fi 4 F t f th i i h i h t f il (CHF) III l t t th h ld (Tl ) Th1015
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lactate threshold and presence ofVO2 slow component at very low work rates include: decreased bulk1021
blood flow and O2 delivery, reduced capillarity, impaired capillary hemodynamics, lowered1022
microvascular PO2, mitochondrial dysfunction particularly in slow twitch highly oxidative (Type I) fibers.1023See text for additional details.1024
Figure 5. Upper panel: Chronic heart failure (CHF, moderate severity, left ventricular end diastolic1025
pressure ~10 mmHg) abolishes the rapid increase in spinotrapezius capillary red blood cell (RBC) flux1026
found in the healthy control muscle following onset of 1 Hz contractions (time 0 s, ref. 136). Lower1027
panel: Microvascular PO2 (PmvO2) profile in the same spinotrapezius preparation. Note that in CHF1028
PmvO2 is lower than for the healthy muscle and there is a transient dip below the steady-state (both1029
indicative of aQO2m-to-VO2 mismatch). From the data of Copp et al. (33), with kind permission.1030
Figure 6. Left panel: Microvascular PO2 (PmvO2) profiles for 180 s of 1 Hz contractions and 180 s of1031
recovery for spinotrapezius muscles of healthy control and chronic heart failure (CHF) rats. Note that1032
the speed of the on-transient fall () may not be substantially different but that the PmvO2 is lower at1033
rest and throughout contractions and recovery in CHF. There is also a pronounced transient dip below1034
the subsequent steady state value (i.e., undershoot) for the CHF muscle. It is also striking that the1035
recovery kinetics of the CHF muscle are markedly slowed by comparison to the on response and that of1036
the healthy control muscle. Right panel: Spinotrapezius PmvO2 recovery kinetics (MRT, mean response1037
time, time delay + ) was progressively slowed in CHF rats with higher left ventricular end-diastolic1038
pressures (LVEDPs). From Copp et al (33), with kind permission.1039
Figure 7. Muscle blood flow during exercise in chronic heart failure (CHF) is constrained by a plethora of1040
structural, mechanical and functional impediments that act to slow the kinetics of blood flow increase,1041
reduce the magnitude of the exercise hyperemia and perturb the matching between O2 delivery and1042
VO2. Pressure, pressure differential along vessel; SNS, sympathetic nervous system; CPCs, circulating1043
endothelial progenitor cells. Sign (- or +) indicates action to decrease or increase blood flow, red arrow1044
gives CHF effect. Inset (bottom right): Effects of CHF on eNOS-derived NO; eNOS, endothelial NO1045
synthase; BH4, tetrahydrobiopterin; ONOO-, peroxynitrite; O2
-, superoxide; SOD, superoxide dismutase;1046
H2O2, hydrogen peroxide; OH-, hydroxyl radical; TNF-, tumor necrosis factor ; IL-1, interleukin-1;1047
ROS, reactive oxygen species.1048
Figure 8. Endurance exercise training opposes many of the dysfunctional elements of chronic heart1049
failure (CHF) and facilitates improved skeletal muscle blood flow (Q
m), pulmonary gas exchange (VO2)1050
and exercise tolerance. Note that the scope of these exercise training adaptations presents a1051
substantial challenge to current and future pharmacotherapeutic approaches to treating CHF patients1052
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EFFECTS OF CHF ON O2 TRANSPORT PATHWAY
HEART/BLOOD
LUNGSPulmonary vascular pressures
Stiffness
VA/Q mismatch
VE (mild hyperventilation)
Diffusing capacity
Car ac output stro e vo ume, e ect on ract onCardiac remodelling,LVEDP
Systemic vasoconstriction (SNS, humoral, reflex, structural)
Impaired cardiac output distribution, pro-inflammatory state
Anemia decreased O2 content.. .
Respiratory muscles
steal blood from
locomotory muscles
veo ar-ar er a 2 gra en
Respiratory muscle work
SKELETAL MUSCLEBlood flow
Vasoconstriction/Vasodilation
Endothelial function,Muscle pump,
Working locomotory muscles
com ete less effectivel for
Metaboreflex, Vascular stiffness,
Myocyte apoptosis, Atrophy,Type II
fibers,Mitochondrial volume
Capillarity,%Capillaries flowing,
Capillary RBC flux
O2 Diffusing capacity,Microvascular O2. .
reduced cardiac output
Gut and splanchnic organs
ma be h erconstricted
2 2Intracellular O
2
pressures,
Glycolytic stimulation/Glycogen depletion
NO bioavailability (extracellular),iNOS,
Cytokines (IL-1, TNF, IL-10),
ROS ( nitrotyrosine,catalase, GPX),
SOD (CuZn),Sympatholysis,VO2 requirement (contractile apparatus,
VO2 slow component)
Figure 1
..
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Reduced VO2max from impaired muscle
O2 delivery and diffusing capacity.
.
(VO
2)
.
2 2
O2 diffusing capacity (DO2)
ea t y
VO2max.
Uptak
VO2max.
Oxyge
CHF Healthy
Microvascular PO2 (PmvO2)
Figure 2
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VO2 kinetics become O2 delivery-dependent and slowed
proportionally with lowered rate of O2 delivery
.
nstant
O2 delivery
dependent zone
2TimeC
(
)
Healthy
O2 delivery
V
Myocyte O2 delivery
n epen en zone.
(%)
Healthy
CHFCHF
VO
2
.
Inadequate O2 delivery slows VO2 kinetics causing:
O2 deficit,PCr,ADPfree, Lactate,H+
.
Time (s)
060 120 180 240
Figure 3
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Lowered lactate threshold reduces the work rate (and VO2)
at which the VO2 slow component emerges elevating the O2.
.
HEALTHY
.
2
2
VLactate
threshold
.
CHF
VO2 VO
2max
.
.
Work Rate
Lactate
threshold
Figure 4
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)50 Control
x(RBC/s
30
RBCFl
CHF
30g
)
20 Control
vO2
(mm
Control
0 30 60 90 120 150 180
0
CHFPm
CHF
Figure 5
Time (s)
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40 140
mHg)
25
30
35
s
100
120
.
P< 0.01on ro
mHg)
RT(s)
PmvO2(m
10
15
20 CHF
ecovery
60
80CHF
Pm
vO2
(
ec
overy
Control
0 60 120 180 240 300 360
0
5
RecoveryContractions
0 10 20 30 40 50
0
40
Severe CHF
mm g
Figure 6
KEY FACTORS MODULATING THE MUSCLE BLOOD FLOW RESPONSE TO EXERCISE IN CHF
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KEY FACTORS MODULATING THE MUSCLE BLOOD FLOW RESPONSE TO EXERCISE IN CHF
Myogenic Muscle Perfusion Post-capillary Vascular
autoregulation pump pressure resistance stiffness
- + +
SNS
-adrenergic -adrenergic
- + - -
Smooth muscle
Endothelium CPCs
Lumen Vascular x Pressure = Blood flow
BH4
Inflammatory/
Cytokine
HumoralCatecholamines - Metabolites+Hypoxia
An iotensin II - Lactate +TNF -
IL 1 -
ROS -
Peroxynitrite -Figure 7
Arg. vasopressin - H+ +
Endothelin-1 - Adenosine +
Inorganic phosphate +Nitric oxide + Potassium +
EXERCISE TRAINING IN CHF
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LV remodelling, LV size, LVEDP, ?()
dp/dt,Ejection fraction, Stroke volume,
?()HRmax,Max cardiac output,
EXERCISE TRAINING IN CHF
TNF,IL-1,IL-6 (background), IL-6
phasic, IL-10, Ilra, Soluble TNF receptors I and
-ar ac output net cs, n ot e um-
mediated coronary dilation, Total peripheral
resistance. Refs. 30,43,49,64,74,77
, ,
Promote anti-inflammatory state. Refs. 1,2,14,32
NAD(P)H oxidase/ gp91phox in RVLM,
SOD (CuZn+Mn) in RVLM
Arterial baroreflex sensitivity/control
Sympathoexcitation/vasoconstriction
. . , ,
Vascular pressures, V/Q mismatch,
Stiffness,Diffusing capacity,
Pulmonary artery resistance/pressure
Alveolar-arterial O2 gradient
Respiratory Muscles
Baroreflex,Chemoreflex
Refs. 123,164
. .
.
, 2. . ,
Sympathoexcitation/vasoconstriction. Refs. 6 7
Systemic arterial compliance, CPCs,
Endothelium-mediated vasodilation,NO bioavailability, BH ,ROS,
Blood flow, Vascular resistance, Capillaries
per fiber, Mitochondrial volume/oxidative
enzyme activity, ?Type II fibers, ?%Capillaries
flowing, ?Capillary RBC flux, ?()O2 diffusing
capacity, ?()O2 delivery-VO2 matching,
?()PmvO2, NO bioavailability (extracellular),iNOS,Cytokines (IL-1, TNF, IL-10),
.
. . ,Catecholamines, Endothelin-1,
Angiotensin II,Arginine vasopressin,
BNP,NT-proBNP, ?Anemia,
Circulating cytokines
Refs. 16,25,29,30,34,37,54,55,62,68,
74,97,102,104,106,140,161
ROS(Nitrotyrosine,Catalase and GPX),
SOD (CuZn), ?()Sympatholysis,Endothelium-
mediated vasodilation, Vascular stiffness,
?()Muscle pump, Metaboreflex,
Apoptosis/atrophy . Refs. 6,7,15,64,65,107,143,
Speed VO2 kinetics
VO2max
Lactate Threshold
O2 cost of exerciseRefs. 6,74,78,119,129,130
.
.
Exercise Tolerance
Figure 8