Am J Physiol Heart Circ Physiol 2011[1]

7/29/2019 Am J Physiol Heart Circ Physiol 2011[1]

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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

[email protected]

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


36/39

)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

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