Articles in PresS. Am J Physiol Heart Circ Physiol (November 18, 2011). doi:10.1152/ajpheart.00943.

2011

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MUSCLE OXYGEN TRANSPORT AND UTILIZATON IN HEART FAILURE: IMPLICATIONS FOR EXERCISE (IN)TOLERANCE

David C. Poole, Daniel M. Hirai, Steven W. Copp, and Timothy I. Musch

Departments of Anatomy, Physiology & Kinesiology, Kansas State University, Manhattan, KS 66506-5802

David C. Poole Department of Anatomy and Physiology College of Veterinary Medicine Kansas State University Manhattan, KS 66506-5802 poole@vet.ksu.edu

Copyright 2011 by the American Physiological Society.

25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 Abstract The defining characteristic of chronic heart failure (CHF) is an exercise intolerance that is linked inextricably to structural and functional aberrations in the oxygen (O2) transport pathway. CHF reduces muscle O2 supply whilst simultaneously increasing O2 demands. CHF severity varies from moderate to

severe and is assessed commonly in terms of the maximum oxygen uptake ( V O2max, which relates
closely to patient morbidity and mortality in CHF and forms the basis for Weber and colleagues

classifications of heart failure, 167), speed of the V O2 kinetics following exercise onset and during
recovery and the capacity to perform submaximal exercise. As the heart fails cardiovascular regulation shifts from controlling cardiac output as a means for supplying the oxidative energetic needs of exercising skeletal muscle and other organs to preventing catastrophic swings in blood pressure. This shift is mediated by a complex array of events that includes altered reflex and humoral control of the circulation, required to prevent the skeletal muscle sleeping giant from outstripping the pathologically-limited cardiac output (QTOT), and secondarily impacts lung (and respiratory muscle), vascular and locomotory muscle function. Recently, interest has also focused on dysregulation of inflammatory mediators including tumor necrosis factor (TNF) and interleukin 1 (IL-1) as well as reactive oxygen species (ROS) as mediators of systemic and muscle dysfunction. This brief review

focuses on skeletal muscle to address the mechanistic bases for the reduced V O2max, slowed V O2
kinetics and exercise intolerance in CHF. Experimental evidence in humans and animal models of CHF unveils the microvascular cause(s) and consequences of the O2 supply (decreased)-O2 demand (increased) imbalance emblematic of CHF. Therapeutic strategies to improve muscle microvascular and oxidative function (e.g., exercise training and anti-inflammatory, antioxidant strategies, in particular) and hence patient exercise tolerance and quality of life are presented within their appropriate context of the O2 transport pathway. Key words: Congestive heart failure; Oxygen uptake kinetics; Maximal oxygen uptake; Exercise training; Muscle microcirculation

52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 At the proximal end of the O2 transport pathway in the lung, CHF patients develop pulmonary dysfunction including ventilation-perfusion (VA/Q) mismatch accompanied by reduced O2 diffusing capacity (5,83-85,170, rev. 126) and diminished respiratory endurance (112). Whereas the VA/Q are accompanied by a chronic hyperventilation resulting from sensitization of the peripheral chemoreceptors (carotid bodies, 151) that, in concert with restrictive and obstructive pulmonary abnormalities, increases the work of breathing (rev. 126). During severe intensity exercise in health the 3 Chronic Heart Failure A Perfect Storm of Multiple Organ System Dysfunction As the heart fails, following a myocardial infarction or other etiology, QTOT at rest, and particularly during muscular exercise, is reduced consequent to a diminished ejection fraction, stroke volume and a heart rate response that is insufficient to compensate for the reduced stroke volume. This is the initiating condition for a cascade of events that affects multiple organ systems (Figure 1, rev. 129,130). There is a global sympathetically-mediated vasoconstriction, that serves initially to maintain QTOT at pre-pathology levels and which subsequently impairs the ability to distribute and redistribute QTOT to and within skeletal muscle(s) (Qm, 120,124,160,173). Enhanced humoral mediators including altered circulating angiotensin, norepinephrine, endothelin-1 (154) and vasopressin levels also contribute to the systemic vasoconstriction in CHF and intravascular sodium and water retention act to further impair vasodilation (177) as do a plethora of events within the peripheral vasculature (vide infra, 25,44,45; rev. 129,130). In addition, Group III (mechanosensitive) and IV (metabosensitive) afferents within the contracting muscles increase global sympathoexcitation (9,35, rev. 164). In support of Coats et al.s muscle hypothesis (31) for CHF Wang et al. (164) have demonstrated that CHF sensitizes Group III afferents which likely contributes to the exaggerated exercise pressor response (EPR). Despite the same studies

demonstrating that Group IV afferents are desensitized in CHF it is pertinent that the far slower V O2 kinetics, lower V O2 and microvascular PO2 (Figures 2-6) will all exacerbate production and accumulation
of metabolites that ultimately stimulate these afferents. Thus, despite their relative desensitization the role of the Group IV afferents in the EPR is likely substantial in CHF. This eventuality would certainly help

explain how exercise training-induced speeding of the V O2 kinetics (131,139) reduces or even prevents
a greater EPR in CHF (165).

mismatch and diffusional impairments are often so mild that they do not cause arterial hypoxemia they

82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109

diaphragm and other respiratory muscles can steal Q from the locomotory muscles (79). In CHF this effect is accentuated (122,126) redistributing more QTOT towards the respiratory muscles and, by

heightening sympathetic vasoconstriction of locomotory muscles, further impoverishing their Qm and O2 supply and compromising exercise tolerance. This condition may be exacerbated further if CHF is accompanied by anemia secondary to dysfunctional iron metabolism and heightened inflammatory stress (103). Furthermore, within skeletal muscles in CHF the capacity to utilize O2 is impaired with reductions in mitochondrial oxidative enzyme activity and volume density as well as mitochondrial dysfunction (e.g., 41,58,65,78,153). It is pertinent that, although skeletal muscle capillarity may (e.g., 171) or may not (58) be reduced significantly, across control and CHF populations the number of capillaries per fiber correlates highly with mitochondrial volume density (58). In addition, CHF increases the proportion of capillaries that do not support red blood cell (RBC) flux at rest and during contractions (137). Impact on Exercise Responses

Four key parameters of aerobic function are the maximal V O2 ( V O2max), V O2 kinetics, V O2 gain (e.g.,
ml O2/watt/min for cycling, an approximate measure of efficiency), and the lactate (Tlac) or gas exchange (GET) threshold (131,133-135,139,168,169). These parameters define the gas exchange (i.e.,

V O2) response to exercise in the transient (i.e., following exercise onset, non-steady state) and steady
state conditions, and, as such, link tightly with exercise tolerance or impediment thereof.

V O2max V O2max has historically been considered the sentinel parameter of integrated cardiovascular function
and has been used widely to judge the severity of CHF (52,71,98,109,111,167,168). Specifically, Class A,

V O2max > 20 ml/kg/min, Class B, 16-20, Class C, 10-15, Class D, <10 which correspond broadly to the
NYHA classifications I, II, III and IV, respectively (167). Accordingly, it is instructive to consider the

determinants of V O2max and what insights these can provide into the mechanisms by which CHF
compromises systemic and muscle O2 transport. Wagner (138,162,163) has championed the notion that, although perfusive cardiovascular O2 delivery

may be the strongest determinant of V O2max in young healthy individuals exercising at sea level
(evidenced by inspired hyperoxia (94), pericardectomy (152), blood doping (70) and small muscle mass

110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134

exercise (137) all increasing V O2max or muscle specific V O2max), pulmonary and muscle diffusive O2 capacities also contribute importantly to V O2max. Moreover, at altitude, after exercise training and in extremely fit individuals (high V O2max) the relative importance among O2 perfusive and diffusive capacities with respect to determining V O2max may shift. In CHF it was traditionally thought that

V O2max was reduced solely consequent to the lowered QTOT and resultant Qm (perfusive O2 transport)

which was supported by the low venous O2 contents measured either centrally (pulmonary artery) (167) or in the exercising muscle(s) effluent venous blood (88). Specifically, the ability to reduce venous O2 content and increase fractional O2 extraction (arterial-venous O2 difference) to a similar (or better) extent as seen in healthy subjects led to the presumption that the effective muscle O2 diffusing capacity (DO2m) was unimpaired. However, as can be seen from Figure 2, the Fick principle:

V O2 = Qm x (arterial - venous O2 content)

and Ficks law of diffusion:

V O2 = DO2m x (microvascular PO2 intramyocyte PO2) conflate to yield V O2max where the curved lines represent perfusive O2 transport (QO2m = Qm x
arterial O2 content) and the straight lines from the origin represent DO2m. Therefore, venous O2 content

(or microvascular PO2 (PmvO2) as shown) in CHF can either be normal or lowered at V O2max even in the
presence of a substantially decreased DO2m. This effect is seen for large muscle mass exercise (e.g., conventional cycling) and small muscle mass exercise (i.e., knee extension) (58). The precise microvascular mechanisms for the reduced DO2m in CHF involve impaired capillary hemodynamics at rest and during contractions and are considered in detail below (see Skeletal Muscle Blood Flow, Capillary Hemodynamics and Microvascular PO2). What should be appreciated from Figure 2 is that, with respect to fractional O2 extraction and thus PmvO2 and venous PO2, there is an interdependence between the muscle perfusive (QO2m) and diffusive (DO2m) relationships that may be expressed as (138):

O2 extraction = V O2/QO2m = QO2m(1-e-DO2m/

Qm

135 136 137

where QO2m is muscle perfusive O2 delivery, DO2m is muscle O2 diffusing capacity, is the slope of the O2 dissociation curve in the physiologically-relevant range and Qm is muscle blood flow. Thus, because there is a substantial reduction in Qm with CHF, DO2m may be compromised and O2 extraction either 5

138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166

normal (ratio DO2m/Qm ) or, as shown in Figure 2, increased (ratio DO2/Qm). The importance

of the reduced DO2m in CHF is evident when vasodilator treatment increases QO2m but not V O2max (47,48). To maximize their beneficial effect on V O2max therapeutic interventions should effectively
increase both perfusive (QO2m) and diffusive (DO2m) O2 transport.

V O2 Kinetics Healthy individuals, let alone CHF patients, rarely exercise at V O2max yet daily activities require myriad increases (and decreases) in metabolic rate and hence V O2. The speed of these adjustments define ones V O2 kinetics in terms of the overall time constant (, time to reach 63%) of the response which
may be 20-30 s in young healthy individuals but slowed to several minutes in CHF patients (Figure 3,

81,118,147,148). Importantly, the speed of the V O2 kinetics has been considered to have even better prognostic value in CHF than V O2max (on-kinetics, 142; off-kinetics, 125). Both the close-toinstantaneous Phase I (driven predominantly by increased pulmonary blood flow, omitted from Figure 3

for clarity) and the subsequent primary (Phase II) response, thought to reflect the muscle V O2 kinetics (72), are impacted by CHF (148) reflecting a failure to both increase QTOT and muscle V O2. The importance of this slowed V O2 kinetics is that the steady state O2 requirement for a given task will
almost certainly be no lower (and may even be higher, see below) in CHF and so, for any given metabolic transition, the CHF patient will incur a greater O2 deficit and therefore more extreme intracellular perturbation of high energy phosphagens and acid-base (Figure 3). Importantly, the greater substrate-

level phosphorylation associated with slower V O2 kinetics accelerates glycogenolysis and contributes to fatigue and the ensuing exercise intolerance (123,131,139). For a given metabolic transition ( V O2) the O2 deficit incurred may be estimated as: V O2. Thus, for the same metabolic transition of, for example,
1 l O2 the healthy individual with fast kinetics ( = 30 s or 0.5 min) will incur an O2 deficit of 0.5 l O2 (0.5x1.0) whereas for the CHF patient with slowed kinetics ( = 120 s or 2 min) their deficit will be 2 l O2 (2.0x1.0) and consequently a muscle biopsy of the patients working muscles would reveal lower [PCr] and a greater [ADPfree] thus resulting in a higher rate of glycogenolysis and [H+]. For locomotory muscles exercise such as cycling, walking or running in young relatively fit healthy

individuals a compelling weight of evidence supports that V O2 kinetics are not limited by muscle O2
delivery but rather subject to mitochondrial control (O2 supply independent zone of Figure 3, refs.

131,139). In contrast in CHF, the pathognomonically-lowered QO2m slows V O2 kinetics creating an O2

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supply dependency (O2 delivery dependent zone, Figure 3). The direct consequences of this slowed V O2
kinetics in CHF and other diseases/conditions are a greater psychological perception of effort, greater intracellular perturbation of phosphagens, acid-base and glycogen and a related decrease in exercise tolerance (see Figure 13 of ref. 139).

V O2 Gain and the Slow Component of V O2 Kinetics

For exercise above the lactate threshold (>Tlac i.e., in the heavy or severe intensity domains) an

additional V O2 cost (or slow component) becomes evident beyond the faster primary (Phase II) kinetics as V O2 rises considerably above the ~10 ml O2/watt/min gain characteristic of moderate (<Tlac) exercise (Figure 4, refs. 80,86,134,135,169). This extra V O2 arises predominantly from within the exercising
muscles and is attributed to a combination of fatigue-related processes necessitating additional fiber recruitment and also metabolic processes occurring within already recruited fibers (133,159). In healthy individuals this slow component may exceed 1 l O2/min, reduce exercise efficiency, and for severe exercise (i.e., above the critical power, the asymptote of the hyperbolic relationship between power

output and time to exhaustion for high intensity exercise), drive V O2 to V O2max heralding imminent
fatigue (135, rev. 86). For the CHF patient, whose Tlac (69,89,178) and critical power (131,139) often

reside at perilously low absolute V O2s, the slow component represents a metabolic extravagance that
they can ill afford. Indeed, the presence of Tlac and critical power in CHF patients at metabolic rates

( V O2s) far lower than seen in healthy individuals means that patients in whom muscle O2 delivery is
most compromised may actually have the highest O2 requirement for muscular exercise (including a higher O2 cost incurred by the respiratory muscles, 126) even at very low work rates. As documented

initially by Zelis and colleagues (173) the actual V O2 achieved by the CHF patient during exercise may be
lower than that for their healthy counterpart. Given the above, this should not be taken as evidence that the CHF patient is working more efficiently. Indeed, the opposite may be the case and the lower

achieved V O2 means that the patient is accumulating a greater (and continuous) O2 deficit leading to
premature exhaustion. To understand the mechanisms underlying the exercise intolerance of CHF the bases for the decreased

V O2max, slowed V O2 kinetics, lowered Tlac and critical power and increased V O2 gain must be explored. As will be seen these bases emerge strongly from compromised Qm and an inability to temporally and spatially match QO2m to requirements ( V O2).
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Skeletal Muscle Blood Flow, Capillary Hemodynamics and Microvascular PO2 (PmvO2) Healthy In health with normal arterial O2 content (~20 ml O2/100 ml), QTOT and Qm increase between 5 and 6 l

per l V O2 (rev. 60). Following the onset of muscular exercise the QTOT increase is extremely rapid owing
to an essentially instant vagal withdrawal accelerating heart rate (Phase I) with a subsequent increase in stroke volume and further elevation of heart rate (Phase II) driving QTOT and Qm kinetics that are

appreciably faster than their V O2 counterparts (40,95,133,157,172). This profile supports the O2

delivery independence of V O2 kinetics in healthy young individuals (Figure 3, refs. 133,139). Thus, Qm
may increase sufficiently fast for moderate (72) as well as heavy and severe exercise (13,96) such that

increased QO2m exceeds muscle V O2 and consequently effluent venous O2 content increases
transiently as fractional O2 extraction is decreased. There is evidence that both rapid arteriolar vasodilation (19, rev. 28) and muscle pumping action (rev. 157) contribute to this almost instantaneous (within 1 s) increase in muscle (95,157) and capillary (92) Q.

Across muscles of different fiber type composition the proportionality of the increase in Qm to V O2 is
similar but fast twitch muscles have a lower Qm at rest such that PmvO2 is lower (and fractional O2 extraction higher) at rest and low metabolic rates than for slow twitch muscles (23,60,117). These fast twitch muscles may have a slower rate of Qm increase following the onset of contractions and be forced to rely more heavily on O2 extraction than slow twitch muscles (23,117). Importantly, as most skeletal muscle capillaries may support red blood cell (RBC) flux at rest the increased Qm with contractions represents augmented RBC flux (and velocity) within already flowing capillaries (92,132). Thus, following the onset of contractions increased blood-muscle O2 flux (diffusional O2 capacity, DO2m) occurs via a combination of (132): 1. Increased RBC flux and velocity in individual capillaries. 2. Recruitment of additional capillary exchange surface by elevating capillary hematocrit and the length of capillary over which O2 flux occurs (i.e., longitudinal recruitment). 3. Reduction of intramyocyte PO2 to establish a sufficient capillary-mitochondrial O2 gradient. 4. Myoglobin deoxygenation to enhance intramyocyte O2 movement. Chronic Heart Failure CHF may attenuate or even abolish the initial rapid increase in QTOT (and thus Qm, 146) following exercise onset (i.,e., Phase I, 148) and result in an extremely slow and often inadequate subsequent 8

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elevation of Qm (Phase II, 108,174-177). For a share of this reduced QO2 exercising skeletal muscle must overcome exaggerated sympathetic, humoral and reflex-mediated vasoconstriction to compete with elevated energetic (and Qm) demands of the respiratory muscles (122,126) and an altered distribution of available QTOT among active locomotory muscles based, in part, upon their fiber type composition (i.e., greater Qm to low oxidative Type II and lower Qm to Type I/oxidative Type II muscles

and muscle fibers in CHF versus healthy animals, 51,124). At V O2max the reduced QTOT (and any
decreased arterial [O2]) lowers QO2m whereas subsequent redistribution of that lowered QTOT away from the major locomotory muscles provides an additional constraint on QO2m (122,126, Figure 2). Compounding these QTOT distributional problems, arterioles within the active muscles themselves have an inherently greater vasoconstrictor tone (44,45) At the muscle capillary level CHF promotes capillary involution (171) and reduces the percentage of capillaries that support RBC flux at rest and during contractions (136). Crucially, those capillaries that do not flow at rest remain stagnant during contractions and this helps place a low limit on DO2m (see Figure 2) as it lowers the number of oxygenated RBCs in the capillary bed at a given moment and therefore available to contribute to the instantaneous blood-myocyte O2 flux. Figure 5 (top) demonstrates that, even in those capillaries that do support RBC flux at rest, the response to

contractions is extremely sluggish. Consequently, even though mitochondrial V O2 kinetics may be impaired in CHF (and especially severe CHF, 41), QO2m kinetics are more affected and the QO2m/ V O2
ratio falls much lower driving PmvO2, either transiently (moderate CHF in young animals, Figure 5 (bottom), 46) or during the steady-state (severe CHF, old animals, 21 cf. 18,22), to extremely low values. Importantly, muscles comprised predominantly of slow twitch fibers are impacted most drastically (20). Thus, compared with healthy muscles, in CHF the PmvO2 (driving blood-myocyte O2 flux) is lowered at

that time when muscle V O2 is, or should be, increasing most rapidly with the result that V O2 kinetics
become O2 delivery (i.e., QO2m) limited and very slow (Figure 3). This response is akin to the overshoot of the muscle hemoglobin+myoglobin deoxygenation profile measured by near-infrared spectroscopy by Sperandio and colleagues (150) in CHF patients. In an attempt to preserve the bloodmyocyte PO2 gradient in the face of falling PmvO2 intramyocyte PO2 is likely to decrease and exacerbate intracellular perturbations of high energy phosphates ([PCr], [ADPfree]), glycolysis and acid-base (8). Not only is this situation sowing the seeds for premature fatigue in CHF but it presages an extremely

slow recovery as seen for PmvO2 in Figure 6. The inability to increase the QO2m delivery/ V O2 ratio
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earlier or faster following cessation of muscle contractions in CHF keeps PmvO2 low, reduces

intramyocyte PO2 and retards V O2 and PCr recovery kinetics (89,90). It is pertinent that recovery V O2
kinetics can often be determined with greater fidelity and reproducibility than its counterpart at the

beginning of exercise (89,90). Thus, altered off-transient V O2 kinetics, sometimes in the presence of
indiscernibly different on-kinetics, may identify O2 transport/utilization derangements in CHF patients (147) and therefore correspond more closely with the extent of functional compromise (39,90,125). This effect has also been demonstrated for the dynamics of muscle PmvO2 as seen in Figure 6 (left panel) for severe CHF (33). Notice the lowered PmvO2 at rest and during contractions in CHF and the PmvO2 undershoot present in the response. However, the most pronounced difference in the kinetics of the PmvO2 response is evident in the off-transient (i.e., recovery) where the control muscle recovers to baseline well before its CHF counterpart has reached 50% recovery. It is pertinent that Copp et al. (33) demonstrated a strong correlation (Figure 6, right panel; r = 0.76, P<0.05, n= 16, control, moderate CHF, severe CHF) between the slowed PmvO2 off-kinetics and elevated left ventricular end-diastolic pressure (LVEDP) albeit driven principally by the severe CHF animals. This observation is relevant because CHF patients often complain of prolonged fatigue that resolves very slowly following exercise or rehabilitation therapy. Ameliorating these symptoms may help improve exercise rehabilitation retention and thus efficacy in the CHF patient community.

Tlac (expressed as the V O2 at which blood lactate begins increasing above values at rest, used here

QO2m, PmvO2 and muscle oxidative capacity (rev. 166). As detailed above, each of these variables is impaired in CHF and, compounded by slowed V O2 kinetics, it is inevitable that Tlac occurs at extremely
low V O2s in CHF patients (69,89,178). Moreover, because of the increased respiratory muscle V O2
(126) as well as any sympathetic stimulation of metabolic rate and/or cachexia the range of achievable sub-Tlac work rates may be disappearingly small. Hence, daily tasks or activities that are sub-Tlac for

synonymously with the gas exchange threshold, GET) is exquisitely sensitive to arterial O2 content,

healthy individuals invoke a systemic lactic acidosis and will therefore incur an extra V O2 cost associated with the V O2 slow component in CHF patients (86,131,133). With their low V O2max (and thus modest Tlac- V O2max range) it is doubtful whether the slow component effect would be as large as seen in
healthy/fit individuals. However, in-and-of itself, this would be expected to accelerate exhaustion especially if it increases the gap between muscle ATP requirements and that generated by oxidative metabolism thereby more rapidly depleting finite non-oxidative muscle energy stores (86,131,135).

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Mechanisms Limiting Increases of Muscle Blood Flow (Qm) in CHF Almost every aspect of Qm control is disturbed in CHF as seen in Figure 7. Vasoconstriction is enhanced by sympathetic nervous system-mediated -adrenergic tone (consequent to enhanced peripheral chemoreceptor sensitivity and heightened metaboreflexes) and increased circulating catecholamines, angiotensin II, arginine vasopressin and endothelin-1 (25,154 rev. 129,130). The efficacy of the muscle pump is impeded by elevated post-capillary resistance (115,146,174,175) and increased vascular stiffness. Endothelial function is compromised by endothelial cell damage and impaired repairability, in part, due to low circulating endothelial progenitor cells (CPCs, 54). Nitric oxide (NO) bioavailability is compromised which presumably constrains sympatholysis (the ability to oppose -adrenergic

vasoconstriction, 155) and shear stress-mediated vasodilation. In turn, inadequate Qm and QO2m will promote hypoxic vasodilation and increase vasodilatory metabolite efflux from the contracting muscle(s) (lactate, H+, adenosine, inorganic phosphate, potassium). The eventual outcome (i.e., reduced

Qm and particularly PmvO2) in CHF indicates that the net balance favors reduced vascular perfusion and impaired QO2m.
Within muscle and other tissues CHF increases TNF and IL-1 levels and the anti-inflammatory

interleukin 10 (IL-10) may decrease (14,54) irrespective of whether circulating concentrations are altered. There is also an aggravated oxidant-antioxidant imbalance. All of these changes can impact NO bioavailability and, given the importance of decreased NO bioavailability in muscle and exercise

dysfunction in CHF (see Role of NO in Regulating Contracting Muscle QO2/ V O2 Matching below), have
been the subject of significant attention.

Role of NO in Regulating Contracting Muscle QO2/ V O2 Matching NO bioavailability can exert a commanding role in the matching of QO2m to V O2 in contracting rat
muscle. For example, Hirai and colleagues (82) have determined in rats that NO-mediated vasodilation helps regulate the distribution of QO2m among active muscle fibers based upon their oxidative capacity. In CHF the capacity for L-NAME (NG-nitro-L-arginine-methyl-ester) blockade of NO synthase (NOS, nonspecific isoform blockade) to reduce Qm, particularly to more highly oxidative muscle fibers, is substantially lessened (82). Using the superfused contracting spinotrapezius preparation NOS blockade transforms the healthy rat PmvO2 profile into one resembling CHF (Figures 5 and 6, refs. 59,61). Moreover in CHF muscles the NOS blockade effect is greatly reduced and application of sodium 11

315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344

nitroprusside (an NO source) restores the PmvO2 profile from that present in moderate CHF back to that seen in the healthy animals (59). However, it must be acknowledged that elevating intracellar [NO] has

the potential to decrease mitochondrial V O2 (10,11,100) and hence restore the healthy QO2m/ V O2
ratio by decreasing the denominator as well as increasing the numerator. Notwithstanding this concern, it is evident that increased NO bioavailability has the potential to enhance blood-myocyte O2 flux in CHF by restoring PmvO2. This potential for compromised NO bioavailability to explain PmvO2 (and thus functional) derangements in CHF highlights the importance of resolving the mechanisms responsible for the reduction in NO bioavailability in CHF and developing/optimizing therapeutic strategies for mitigating this effect (Figure 7, inset (bottom right panel)). Inflammatory Mediators reduce NO Bioavailability in CHF CHF-induced muscle vascular dysfunction and the associated decreased NO bioavailability is mediated, in part, by a combination of the reduction in endothelial cell tetrahydrobiopterin (BH4, an essential cofactor for NOS), superoxide dismutase (SOD), catalase and glutathione peroxidase (GPX) protein expression and activity as well as increased NADPH oxidase protein expression and activity each of which serves to elevate superoxide radicals (O2 -) and decrease NO (Figure 7, inset (bottom right panel), 17,42,82,93,97,106,110). Inflammatory mediators TNF and IL-1 promote oxidative stress and have been heavily implicated in this process (1,2,24,34,53,65,67,105,156,158). Reducing BH4 uncouples endothelial NOS (eNOS) lowering NO production (110,149) and generating O2 - which itself enhances NO degradation and produces the peroxynitrite ROS (Figure 7, inset (bottom right panel), 149). Moreover, enhanced O2 - will, by the action of SOD, elevate hydrogen peroxide (H2O2) which, although a vasodilator in its own right, in the presence of Fe2+ yields the potent vasoconstrictor OH - (hydroxyl radical) via the Fenton reaction. In addition, elevated cytokines (TNF, IL-1) promote iNOS induction such that intracellular [NO] rises and inhibits key oxidative enzymes and mitochondrial creatine kinase (4,65,76) as well as promoting apoptosis (3). In aged rats increased BH4, induced via acute exogenous bolus sepiapterin (substrate for BH4 synthesis) treatment or exercise training, improves NO signaling in skeletal muscle arterioles and restores flowinduced vasodilation (149). Whether this is also the case in CHF is an important question given the commonality between the conditions of aging and CHF with respect to these inflammatory mediators (i.e., TNF and IL-1). It is pertinent that pentoxifylline, a phosphodiesterase inhibitor which also blocks cytokine expression reducing circulating and tissue TNF and IL-1, improves capillary hemodynamics in

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ischemic conditions (in this respect analogous to CHF, 38,50,145) and has demonstrated clinical efficacy in CHF patients (12,145). Pentoxifylline may also help restore more normal skeletal muscle hemodynamics in CHF by reducing the CHF-enhanced sympathoexcitation via central effects within the paraventricular nucleus and elsewhere (75). However, this remains to be empirically determined.

Specific Effects of CHF and Exercise training on Mediators of NO Bioavailability In contrast to CHF, NO bioavailability and endothelial function in skeletal muscle and heart are upregulated by exercise training (73,101,114,144) particularly against a background of CHF (Figure 8, 34,161). The effect of exercise training and its ability to combat the predations of CHF has been attributed, in part, to increased BH4 (16,106), as well as decreased oxidative stress (increased SOD, catalase and GPX, 62,68,102,106,140), reduced TNF and IL-1 (1,32,66,104) and reduced iNOS which decreases intramyocyte [NO] and presumably lessens its pernicious intracellular consequences (65). Moreover, exercise training may increase muscle capillarity (facilitated by preservation of the vascular endothelial growth factor (VEGF) signaling pathway in CHF patients, 57) and oxidative function in CHF patients (56) as it does in healthy individuals (26,141) as well as restore levels of the anti-inflammatory mediator IL-10 (14). In addition, exercise training may improve vascular endothelial function via a c-Srcdependent increase of eNOS expression and NO bioavailability as well as help restore endothelial repair and function by elevating CPCs (37,54,56,62,97,101,114).

Conclusions CHF compromises almost every facet of the O2 transport pathway which can explain much of the

exercise intolerance and premature fatigue in this condition. V O2max is decreased by impaired
perfusive O2 transport to and within the active muscles and also compromised diffusional O2 transport that may result from failure to sustain RBC flux within a substantial proportion of the capillary bed creating a marked temporal and spatial imbalance between O2 delivery (QO2m) and requirements

( V O2). V O2 kinetics become QO2m-limited and grossly retarded at very low metabolic rates thereby
incurring a large O2 deficit, accentuated intracellular metabolic perturbation and enhanced

glycogenolysis. In CHF the lactate threshold (Tlac) occurs at lower V O2s necessitating the metabolic extravagance of the V O2 slow component and raising the V O2 gain (or at least energetic requirement)
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for tasks or activities which constitute moderate exercise (<Tlac, no V O2 slow component) for healthy
individuals. The plethora of structural and functional (neurohumoral, inflammatory, reflex) consequences of CHF coalesce at the muscle microcirculation and abolish the rapid increase of capillary

RBC flux and velocity and RBC distribution necessary to regulate PmvO2 and support fast V O2 kinetics.
Whereas a simple solution to this complex pathology may be overly optimistic, recent empirical

evidence supports an important role for NO bioavailability in matching QO2m to V O2. As such, strategies
that enhance NO bioavailability whilst decreasing the predations of inflammatory cytokines (TNF, IL1) and possibly increasing anti-inflammatory cytokines (IL-10) and CPCs, for example, exercise training (66), pentoxifylline, statins (e.g., rosuvastatin, 54) and antioxidant strategies (but not acute vitamin C, 55) offer hope. In addition, if dietary nitrate supplementation can improve exercise efficiency (reduced

V O2 gain) in CHF patients as it does in healthy individuals (10,11,99,100), QO2m-to- V O2 matching will be enhanced and exercise tolerance might be improved without the necessity for increased Qm, fractional O2 extraction or altered Qm distribution. Finally, the demonstration that vascular signalling mechanisms
are retained in CHF patients (e.g., VEGF, 57) coupled with the ability for ventilatory-assist devices to redistribute QTOT to the locomotory muscles (126) and specific respiratory muscle training to enhance limb Qm and exercise tolerance in CHF patients (27,36,113) suggests innovative strategies for improving cardiac rehabilitation program retention and outcomes. The challenge for physiologists, exercise specialists and clinician-scientists is to resolve the specific mechanisms underlying CHF-induced dysfunction at each step in the O2 transport pathway. This is crucial in order to increase exercise tolerance most effectively in the CHF patient; in this regard it is clear that

even very aggressive contemporary pharmaceutical treatment is not reversing the QO2m-to- V O2
mismatching aberrations in skeletal muscle (150). In turn those improvements in exercise tolerance need to be quantified appropriately (168) and related to the parameters of aerobic function. As proposed by Coats and colleagues (31) skeletal muscle plays center-stage in the dysfunction and prognosis of the CHF patient and recent evidence is emerging for contracting skeletal muscles producing myokines that actively oppose the inflammatory condition of CHF (and other diseases/conditions) (127,128). This is exciting and particularly relevant to CHF because small initial improvements in the O2

transport pathway, insofar as these increase V O2max and Tlac, and speed V O2 kinetics, thereby
improving exercise tolerance, may initiate a positive feedback that eventually reverses many of the predations of CHF. Joyners (87) example of a young man, Chad Carvin, who recovered from heart failure to win a silver medal in swimming (4X200 m freestyle relay) at the 2000 Olympic Games in 14

405 406 407 408 409 410 411 412

Sydney, provides evidence that, beyond the failing heart, the O2 transport predations of CHF are potentially reversible.

Acknowledgments This work was supported, in part, by grants from the National Institutes of Health (HL-50306, AG-19228, HL-108328), the American Heart Association (Grants-in-Aid to D.C.P., T.I.M.), CapesBrazil Fulbright Fellowship program (to D.M.H.).

15

413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456

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985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 Figure Legends Figure 1. Predations of chronic heart failure (CHF) on the O2 transport pathway. Although a dysfunctional heart and impaired ability to generate cardiac output are the core events CHF is a multiorgan disease affecting all steps in the O2 transport pathway. CHF-induced lung dysfunction redistributes blood flow (Q) to the respiratory muscles via locomotory muscle vasoconstriction, there may be systemic anemia, systemic vasoconstriction and elevated left ventricular end diastolic pressures as well as a plethora of structural and functional adaptations (increased vasoconstriction, impaired vasodilation and muscle pump) that compromise skeletal muscle perfusional and diffusional O2 transport. See text for more details.

Figure 2. Facets of the exercise response in chronic heart failure (CHF) I: V O2max. Schematic illustrating how the perfusive (curved lines, Fick principle, V O2 = Qm (arterial-venous O2 content)) and diffusive O2 (straight lines from origin, Ficks law, V O2 = DO2m (PmvO2 PintracellularO2)) transport conflate to yield the V O2max during large muscle mass exercise (e.g., cycling). Note that, in CHF (dashed lines), V O2max is reduced by both impaired perfusive and diffusive O2 transport and that PmvO2 may either be the same or lower (arrows on abscissa) than found in health even in the presence of marked diffusional derangements. Mechanisms responsible for these perfusive and diffusive O2 transport derangements include: reduced bulk blood flow and O2 delivery, impaired blood flow distribution, reduced capillarity and percentage of capillaries supporting red blood cell (RBC) flux, lowered functional capillary hematocrit (#RBCs adjacent to contracting myocytes in flowing capillaries) and impaired mitochondrial function. See text for additional details. Figure 3. Facets of the exercise response in chronic heart failure (CHF) II: V O2 kinetics. CHF slows V O2 kinetics (increased time constant, ) in response to moderate (as shown), heavy and severe intensity exercise, in part, by lowering muscle perfusive and diffusive O2 transport such that O2 delivery becomes limiting (top panel, see grey O2 delivery dependent zone). Note that these slowed V O2 kinetics will mandate a greater O2 deficit leading to greater intracellular perturbations that accelerate glycogen depletion and sow the seeds for exercise intolerance. Mechanisms responsible for slowed V O2 kinetics in CHF include: slowed/absent arteriolar vasodilation, impaired muscle pump (venous congestion), slowed capillary hemodynamics, lowered microvascular PO2, impaired mitochondrial function, greater intracellular perturbation (as detailed in bottom panel). See text for additional details.
Figure 4. Facets of the exercise response in chronic heart failure (CHF) III: lactate threshold (Tlac). These curves are constructed from a series of independent constant-work rate exercise tests performed in a healthy individual (upper) and a CHF patient (lower). Note the far lower work rate for the Tlac in CHF

and that the V O2 slow component (grey areas) becomes evident only above Tlac. One consequence of this behavior is that the CHF patient experiences an additional O2 demand at very low work rates that may drive V O2 to V O2max and herald imminent exhaustion. Mechanisms responsible for the lowered
30

1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056

lactate threshold and presence of V O2 slow component at very low work rates include: decreased bulk blood flow and O2 delivery, reduced capillarity, impaired capillary hemodynamics, lowered microvascular PO2, mitochondrial dysfunction particularly in slow twitch highly oxidative (Type I) fibers. See text for additional details.
Figure 5. Upper panel: Chronic heart failure (CHF, moderate severity, left ventricular end diastolic pressure ~10 mmHg) abolishes the rapid increase in spinotrapezius capillary red blood cell (RBC) flux found in the healthy control muscle following onset of 1 Hz contractions (time 0 s, ref. 136). Lower panel: Microvascular PO2 (PmvO2) profile in the same spinotrapezius preparation. Note that in CHF PmvO2 is lower than for the healthy muscle and there is a transient dip below the steady-state (both

indicative of a QO2m-to- V O2 mismatch). From the data of Copp et al. (33), with kind permission.
Figure 6. Left panel: Microvascular PO2 (PmvO2) profiles for 180 s of 1 Hz contractions and 180 s of recovery for spinotrapezius muscles of healthy control and chronic heart failure (CHF) rats. Note that the speed of the on-transient fall () may not be substantially different but that the PmvO2 is lower at rest and throughout contractions and recovery in CHF. There is also a pronounced transient dip below the subsequent steady state value (i.e., undershoot) for the CHF muscle. It is also striking that the recovery kinetics of the CHF muscle are markedly slowed by comparison to the on response and that of the healthy control muscle. Right panel: Spinotrapezius PmvO2 recovery kinetics (MRT, mean response time, time delay + ) was progressively slowed in CHF rats with higher left ventricular end-diastolic pressures (LVEDPs). From Copp et al (33), with kind permission. Figure 7. Muscle blood flow during exercise in chronic heart failure (CHF) is constrained by a plethora of structural, mechanical and functional impediments that act to slow the kinetics of blood flow increase, reduce the magnitude of the exercise hyperemia and perturb the matching between O2 delivery and

V O2. Pressure, pressure differential along vessel; SNS, sympathetic nervous system; CPCs, circulating
endothelial progenitor cells. Sign (- or +) indicates action to decrease or increase blood flow, red arrow gives CHF effect. Inset (bottom right): Effects of CHF on eNOS-derived NO; eNOS, endothelial NO synthase; BH4, tetrahydrobiopterin; ONOO-, peroxynitrite; O2 -, superoxide; SOD, superoxide dismutase; H2O2, hydrogen peroxide; OH -, hydroxyl radical; TNF-, tumor necrosis factor ; IL-1, interleukin-1; ROS, reactive oxygen species. Figure 8. Endurance exercise training opposes many of the dysfunctional elements of chronic heart

failure (CHF) and facilitates improved skeletal muscle blood flow (Qm), pulmonary gas exchange ( V O2) and exercise tolerance. Note that the scope of these exercise training adaptations presents a substantial challenge to current and future pharmacotherapeutic approaches to treating CHF patients (150). References cited for each organ/system are emblematic rather than comprehensive. Note that inspiratory muscle training also increases locomotory Qm, V O2max and exercise tolerance (27,36,113). See text for more details.

31

EFFECTS OF CHF ON O2 TRANSPORT PATHWAY

HEART/BLOOD LUNGS
Pulmonary vascular pressures Stiffness . . VA/Q mismatch . VE (mild hyperventilation) Diffusing capacity Alveolar-arterial O2 gradient Al l t i l di t Respiratory muscle work Respiratory muscles steal blood from locomotory muscles Cardiac C di output ( (stroke volume, ejection f k l j i fraction) i ) Cardiac remodelling, LVEDP Systemic vasoconstriction (SNS, humoral, reflex, structural) Impaired cardiac output distribution, pro-inflammatory state Anemia decreased O2 content

SKELETAL MUSCLE
Blood flow Vasoconstriction/Vasodilation Endothelial function, Muscle pump, Metaboreflex, Vascular stiffness, Myocyte apoptosis, Atrophy, Type II fibers, Mitochondrial volume Capillarity, %Capillaries flowing, Capillary RBC flux O2 Diffusing capacity, Microvascular O2 . . pressures (QO2/VO2 mismatch) Intracellular O2 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)

Working locomotory muscles p y compete less effectively for reduced cardiac output

Gut and splanchnic organs may be hyperconstricted

Figure 1

Reduced VO2max from impaired muscle O2 delivery and diffusing capacity

Oxygen Uptake (VO2) n e

O2 delivery (QO2) O2 diffusing capacity (DO2)

Healthy H lth . VO2max

.CHF VO max
2
CHF Healthy

Microvascular PO2 (PmvO2)

Figure 2

VO2 kinetics become O2 delivery-dependent and slowed proportionally with lowered rate of O2 delivery VO2 Time Co O onstant
O2 delivery dependent zone

CHF Healthy
O2 delivery independent zone

()

Myocyte O2 delivery

Healthy VO2 (%)

CHF CHF
Inadequate O2 delivery slows VO2 kinetics causing: O2 deficit, PCr, ADPfree, Lactate, H+

60

120

180

240 Figure 3

Time (s)

Lowered lactate threshold reduces the work rate (and VO2) . at which the VO2 slow component emerges elevating the O2 demand for submaximal exercise at very low work rates HEALTHY

VO2max

VO2 O

Lactate threshold

CHF

VO2

VO2max

Lactate threshold

Figure 4

Work Rate

50

RBC Flu (RBC/s) ux )

Control

30
CHF

10

PmvO2 (mmH Hg)

30 20 10
CHF CHF Control Control

0 0 30 60 90 120 150 180

Figure 5

Time (s)

40 35

Control Control C t l

140

R Recovery M Recovery MRT (s)(s) M MRT

P PmvO (mmHg) PmvO22(m mmHg)

120 100 80 60 40 0

r = 0 76 0.76 P < 0.01

30 25
20 15 10 5 0 0

CHF CHF

Control Moderate CHF Severe CHF

0 10 20 30 40 50

Contractions
60 120 180

Recovery
240 300 360

Time Time(s) (s)

LVEDP ( LVEDP(mmHg) ) (mmHg) H

Figure 6

KEY FACTORS MODULATING THE MUSCLE BLOOD FLOW RESPONSE TO EXERCISE IN CHF Neural
SNS -adrenergic -adrenergic Myogenic autoregulation Muscle pump

Mechanical
Perfusion pressure Post-capillary resistance Vascular stiffness

Smooth muscle Endothelium

CPCs

Lumen

Vascular x conductance

Pressure

Blood flow
BH4

Humoral
Catecholamines Angiotensin II g Arg. vasopressin Endothelin-1 Metabolites+Hypoxia Lactate + H+ + Adenosine + Inorganic phosphate + Potassium +

Inflammatory/ Cytokine
TNF IL 1 ROS Peroxynitrite -

Figure 7

Nitric oxide +

EXERCISE TRAINING IN CHF

LV remodelling, LV size, LVEDP, ?() dp/dt, Ejection fraction, Stroke volume, ?()HRmax, Max cardiac output, ?()C di output ki i E d h li ?()Cardiac kinetics, Endotheliummediated coronary dilation, Total peripheral resistance. Refs. 30,43,49,64,74,77 TNF, IL-1, IL-6 (background), IL-6 phasic, IL-10, Ilra, Soluble TNF receptors I and II C-reactive protein Adhesion molecules II, C reactive protein, 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 (gut/muscle/skin/general). Refs. 63,129,130 (gut/muscle/skin/general) Refs 63 129 130

Baroreflex, Chemoreflex Refs. 123,164

Vascular pressures, V/Q mismatch, Stiffness, Diffusing capacity, Pulmonary artery resistance/pressure Alveolar-arterial O2 gradient Respiratory Muscles . Refs. 74,77 Blood flow, VO2. Refs 74 77 flow 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 ( , TNF, IL-10), , y (IL-1, , ), ROS(Nitrotyrosine, Catalase and GPX), SOD (CuZn), ?()Sympatholysis, Endotheliummediated vasodilation, Vascular stiffness, ?()Muscle pump, Metaboreflex, Apoptosis/atrophy . Refs. 6,7,15,64,65,107,143,

..

Sympathoexcitation/ vasoconstriction. Refs. 6,7

Systemic arterial compliance, CPCs, Endothelium-mediated vasodilation, NO bioavailability, 4, y, BH ROS, , 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

. Speed VO2 kinetics . VO2max Lactate Threshold O2 cost of exercise

Refs. 6,74,78,119,129,130

Exercise Tolerance Figure 8