TOPICS IN INTEGRATED SYSTEMS PHYSIOLOGY Peripheral limitations of maximal aerobic capacity in patients with chronic heart failure

Stuart D. Katz, MD, and Haoyi Zheng, MD, PhD

Chronic heart failure (CHF) often presents clinically as an exercise-intolerance syndrome with associated congestive signs and symptoms and concomitant left ventricular systolic dysfunction. Although left ventricular ejection fraction (LVEF) is an important marker of disease progression and prognosis, it is generally recognized that resting LVEF or other resting parameters of left ventricular hemodynamic performance are not closely correlated to the degree of exercise intolerance.1,2 The unexpected dissociation between resting LVEF and functional capacity may be partly attributable to poor correlation between resting LVEF and exercise-induced changes in cardiac function. Chronotropic incompetence and the effects of left ventricular end-diastolic volume, mitral regurgitation, and right ventricular function on forward stroke volume are important factors that may contribute to decreased cardiac output reserve during exercise independently of LVEF.3,4 In addition to these hemodynamic factors that reduce cardiac output reserve in CHF, peripheral determinants of oxygen utilization during exercise (skeletal muscle blood ow and oxygen extraction) also play an important role in the pathophysiology of exercise intolerance in patients with CHF. This review will discuss the differential determinants of maximal exercise capacity in healthy subjects and patients with CHF and consider the pathogenesis and diagnostic and therapeutic implications of peripheral limitations of maximal aerobic capacity in patients with CHF. DETERMINANTS OF MAXIMAL EXERCISE CAPACITY IN HEALTHY SUBJECTS In healthy subjects maximal aerobic capacity can be objectively determined by measurement of oxygen uptake with analysis of expired gases during symptomlimited treadmill or bicycle ergometry exercise. Maximal
From the Yale University School of Medicine, Section of Cardiovascular Medicine, Heart Failure Center, New Haven, Conn. Reprint requests: Stuart D. Katz, MD, Yale University School of Medicine, Section of Cardiovascular Medicine, Heart Failure Center, 135 College St, Suite 301, New Haven, CT 06510; stuart.katz@yale.edu. J Nucl Cardiol 2002;9:215-25. Copyright 2002 by the American Society of Nuclear Cardiology. 1071-3581/2002/$35.00 0 43/1/123183 doi:10.1067/mnc.2002.123183

oxygen uptake is characterized by the appearance of a plateau in oxygen uptake at end exercise despite increasing work rate and is highly reproducible.5 The physiologic determinants of maximal oxygen uptake are the maximal cardiac output and the maximal widening of the systemic arteriovenous oxygen difference. During maximal exercise with the lower extremities, when more than 40% of the total skeletal muscle mass is metabolically active, the vasodilatory reserve of the exercising skeletal muscle to accommodate blood ow at normal physiologic pressures is substantially greater than the maximal cardiac output capacity.6,7 Regional distribution of cardiac output during exercise is regulated by a complex interaction of systemic vasoconstriction of non-exercising regions (mediated primarily by the sympathetic nervous system) and regional vasodilation within the active skeletal muscle (mediated by metabolic vasodilation), which delivers nearly 90% of available cardiac output to the exercising skeletal muscle.8 Because arterial oxygen saturation is near 100% and does not change during exercise in subjects with normal gas exchange function, the maximal arteriovenous oxygen difference is determined by increasing oxygen extraction in the exercising skeletal muscle. Oxygen utilization in skeletal muscle during exercise is determined by the factors that regulate mitochondrial oxygen consumption in the myocyte: limb blood ow, capillary volume and hematocrit, capillary diffusion capacity, myoglobin concentration, and mitochondrial respiratory rate.9-11 In healthy subjects the oxidative capacity of skeletal muscle greatly exceeds the maximal delivery rate of oxygen supplied by nutritive blood ow.12 As a result of the effects of transit time and diffusion capacity, healthy subjects extract approximately 75% of available oxygen in the active skeletal muscle circulation at maximal exercise. Because peripheral vasodilatory capacity and muscle oxidative metabolic capacity exceed the blood ow and oxygen delivery capability of the heart, maximal cardiac output reserve is the principal limiting factor of aerobic capacity during maximal exercise in healthy subjects. DETERMINANTS OF MAXIMAL EXERCISE IN CHF Several lines of evidence from clinical studies suggest that cardiac output reserve is not the principal determinant of maximal aerobic capacity in patients with
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CHF, in contrast to healthy subjects. Acute administration of positive inotropic agents (dobutamine) and vasodilators (hydralazine) improves resting and exercise cardiac output but not maximal aerobic capacity in patients with CHF.13,14 Increased mixed venous oxygen content in response to these acute pharmacologic interventions indicates that the augmented cardiac output during exercise is shunted to metabolically inactive tissues. Two studies used manipulations of active skeletal muscle mass rather than drugs to investigate the role of cardiac output reserve versus peripheral factors as determinants of maximal exercise capacity in patients with CHF. In a comparison of blood ow responses to cycle ergometry exercise with 1 leg versus 2 legs, exercising muscle blood ow during 1-leg exercise was greater than that during 2-leg exercise in healthy subjects but not in patients with CHF.15 Failure to augment exercising skeletal muscle ow during 1-leg exercise in patients with CHF demonstrates that a defect in regional skeletal muscle vasodilation, rather than cardiac output reserve, was the principal limitation to leg blood ow. A subsequent report investigated the effect of the addition of upper-limb exercise to maximal lower-limb bicycle ergometry exercise in healthy subjects and patients with CHF.16 Maximal oxygen consumption did not change with the addition of upper-limb exercise to maximal lower-limb exercise in healthy subjects, whereas patients with advanced CHF (peak oxygen uptake 15 mL/kg/ min) had signicantly increased peak oxygen consumption when upper-limb exercise was added to lower-limb exercise (Figure 1).16 The ability to increase oxygen consumption in response to additional active skeletal muscle mass demonstrates that additional cardiac output reserve was recruited to the skeletal muscle circulation of the upper limb. Taken together, the ndings of these studies demonstrate that peripheral limitations of skeletal muscle blood ow and oxygen utilization during exercise, rather than reduced cardiac output reserve, are the principal factors limiting aerobic capacity in CHF. This interpretation is further supported by the observation that restoration of normal left ventricular function after cardiac transplantation does not acutely improve maximal exercise performance.17 Impaired limb oxygen utilization during maximal lower-limb exercise in CHF may be related to vascular or metabolic abnormalities in skeletal muscle (or both). Despite reports of decreased content of skeletal-muscle oxidative enzymes in CHF, oxygen extraction in exercising skeletal muscle is normal or even greater than normal in these patients (Figure 2).18-21 The near-complete extraction of oxygen in patients with most severe limitation of aerobic capacity suggests that reduced capacity of oxidative enzymes in skeletal muscle does not limit maximal exercise capacity in these patients.22

Figure 1. A plot of oxygen uptake (milliliters per kilogram per minute) during maximal lower-limb (LL) exercise (x-axis) and percent change in peak oxygen uptake during combined upperlimb (UL) and maximal lower-limb exercise (y-axis) in healthy subjects (white circles) and patients with CHF (black circles). Peak oxygen uptake increases in patients with moderate to severe aerobic impairment (peak oxygen uptake 15 mL/kg/ min) but not in patients with mild aerobic impairment or healthy subjects. (Used with permission from Jondeau et al. Circulation 1992;86:1351-6.)

Figure 2. A plot of peak oxygen uptake (milliliters per kilogram per minute) and oxygen content of deep femoral vein blood at peak exercise in healthy subjects (triangles) and patients with CHF due to systolic dysfunction (squares) and preserved systolic function (circles). Increased oxygen extraction is present in patients with more severe aerobic impairment. (Used with permission from Katz et al. J Appl Physiol 2000;88:2138-42.)

The maximal vasodilatory response in skeletal muscle circulation to exercise, as well as a diverse array of physiologic and pharmacologic vasodilatory stimuli, is impaired in the skeletal muscle circulation of patients with CHF.7,23 In contrast to abnormalities of left ventricular function, alterations in skeletal muscle vascular conductance are closely correlated to maximal aerobic capacity in patients with CHF.7,8 Increased minimal

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PATHOGENESIS OF VASCULAR CHANGES IN CHF The impaired vasodilatory responses to exercise in patients with CHF have been attributed to sodium and water retention in the blood vessel wall, neurohormonal activation, and intrinsic abnormalities of vascular smooth muscle structure and function.7 In addition, abnormal vascular endothelial function appears to contribute to the impaired peripheral vasodilatory capacity in patients with CHF. The vascular endothelium releases vasoactive substances that play an important role in the normal regulation of peripheral vasomotor tone.32,33 Vascular endothelium dysfunction in patients with CHF is characterized by reduced release of the endothelium-derived relaxing factor nitric oxide and increased release of endothelium-derived vasoconstricting factors including endothelin 1, prostaglandins, and superoxide anion.33 In experimental studies in rats with heart failure after myocardial infarction and in dogs with heart failure induced by rapid ventricular pacing, agonist-stimulated and ow-stimulated nitric oxidemediated vasodilation is decreased in conduit and resistance vessels when compared with normal controls.34,35 Basal endothelial nitric oxide synthesis is decreased in experimental models of heart failure and in patients with CHF.36-38 In patients with heart failure, endothelium-dependent vasodilation in response to muscarinic agonists is impaired in the coronary and skeletal muscle circulations of the upper and lower extremities, when compared with that of healthy subjects.39-41 Shear stress at the endothelial cell surface is a potent stimulus of endothelial-cell nitric oxide synthesis and plays an important role in mediating ow-induced vasodilation during exercise.42 Nitric oxide contributes to the regulation of skeletal muscle blood ow as part of a coordinated regulatory system that preferentially supplies blood ow to muscles with high oxidative capacity during submaximal exercise.43 Exercise-induced nitric oxidemediated vasodilation is impaired in the intact skeletal muscle circulation of rats with heart failure due to experimental myocardial infarction44 and in the forearm skeletal muscle circulation of patients with CHF.45 In patients with CHF, maximal exercise capacity and functional class correlate with the severity of impairment of nitric oxidemediated vasodilation.45-48 Endothelium-dependent changes in arteriolar structure may also limit exercise-induced hyperemia in CHF. The vascular endothelium plays an important role as a paracrine organ in the regulation of the vascular remodeling process.24,49 Reduced peripheral blood ow in association with decreased nitric oxide synthesis and increased synthesis of endothelin 1 and angiotensin II may result in the reduction of the caliber of resistance arterioles in the skeletal muscle circulation of patients

Figure 3. Determinants of vascular remodeling. Blood vessels maintain shear stress at the endothelial cell surface and wall stress within the vascular smooth muscle within a narrow physiologic range by changing the internal diameter and wall thickness of the blood vessels in response to changes in regional ow and pressure conditions and in response to vasoactive endocrine, autocrine, and paracrine substances. NE, Norepinephrine; ATII, angiotensin II; NO, nitric oxide; ET-1, endothelin 1.

vascular resistance in response to maximal vasodilating stimuli suggests that structural changes in resistance arterioles leads to a reduction in the effective crosssectional area of the microcirculation in skeletal muscle in patients with CHF. Blood vessels regulate their caliber and wall thickness to maintain endothelial shear stress and vascular smooth muscle wall stress within narrow physiologic ranges (Figure 3).24-27 Chronically reduced peripheral blood ow, systemic neurohormonal activation, abnormalities in vascular endothelial function (decreased synthesis of nitric oxide and increased synthesis of endothelin 1), and activation of cytokines and local tissue growth factors may reduce the caliber of the resistance arterioles and therefore decrease maximal vasodilatory capacity in the peripheral circulation of patients with CHF. In rats the vascular response to experimental myocardial infarction is characterized by increased stiffness and water permeability in large conduit arteries and increased medial thickness and increased collagen content in resistance arterioles.28,29 In human subjects with heart failure, subintimal hyalinosis and basement membrane thickening have been described in resistance arterioles and capillaries of the skeletal muscle and skin circulation.30,31 The increase in minimum vascular resistance due to these structural changes limits skeletal muscle perfusion during exercise and is an important determinant of reduced maximal aerobic capacity in patients with CHF.

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with CHF, which limits maximal skeletal muscle perfusion (and thus maximal oxygen uptake) during exercise.50 Increased oxidative stress may induce endothelial dysfunction by altering critical signal transduction pathways, by directly decreasing endothelial nitric oxide synthase activity, and by increasing degradation of nitric oxide.51-55 Evidence of increased oxygen free-radical formation has been reported in animal models of heart failure and in patients with heart failure secondary to diverse etiologies, including patients with left ventricular dysfunction with minimal or no symptoms.56-61 Increased formation of oxygen free radicals in heart failure may be related to activation of cytokines, increased activity of the cyclooxygenase pathway, increased synthesis of angiotensin II (via activation of membraneassociated nicotinamide adenine dinucleotide phosphatedependent oxidase), and altered ow pattern in the circulation.62-67 Endothelial cells, vascular smooth muscle, myocytes, macrophages, and neutrophils are potential cellular sources of oxygen free radicals.56,62,68-70 Low-molecular-weight ferrous iron non-enzymatically catalyzes the production of hydroxyl radical from hydrogen peroxide in the Fenton reaction. Hydroxyl radical is a highly reactive species that leads to lipid peroxidation, oxidative damage of DNA, cell dysfunction, and death. Accordingly, reduction in availability of intracellular low-molecular-weight ferrous iron may reduce the toxic effects of hydroxyl radical formation in endothelial cells via the Fenton reaction.71,72 Dexrazoxane is an intracellular iron chelation agent that is currently approved for prevention of anthracycline cardiotoxicity.73,74 Its chelation action protects against oxidative damage by inhibition of formation of toxic anthracycline-iron complexes in myocardium. Whether dexrazoxane offers protection against the damaging effects of iron-dependent hydroxyl radical formation in other tissues and other clinical settings is unknown. THERAPEUTIC IMPLICATIONS Because fractional oxygen extraction in exercising skeletal muscle of patients with severe aerobic impairment is nearly complete, improvement in maximal aerobic capacity in response to therapeutic interventions must be primarily mediated by increased skeletal muscle perfusion. The benecial effects of some established therapies in heart failure may be partly attributable to improved endothelial function. Angiotensin-converting enzyme (ACE) inhibitors, which induce favorable effects on functional capacity, exercise skeletal muscle blood ow, and long-term morbidity and mortality in heart failure, partially reverse vascular remodeling after myocardial infarction in rats, enhance exercise-induced va-

sodilation in patients with heart failure, and enhance endothelium-dependent vasodilation in experimental and clinical studies.29,75-77 Improved endothelial function may account for the reduction in coronary event risk associated with long-term ACE inhibition therapy.78,79 As discussed below, ACE inhibition is also associated with improved skeletal muscle blood ow during exercise. Physical training, which increases peak aerobic capacity, increases skeletal muscle vasodilatory reserve, and improves outcome in patients with heart failure, also enhances endothelium-dependent vasodilation in the skeletal muscle and coronary circulations.80-85 Impaired endothelium-dependent vasodilation in CHF is attributable to reduced synthesis and bioavailability of nitric oxide and reduced cyclic guanosine monophosphate dependent vasodilation in vascular smooth muscle.36,41 Cyclic guanosine monophosphate levels in vascular smooth muscle are regulated by their production by guanylyl cyclase and their degradation by type-5 phosphodiesterase. Decreased vasodilation response to endogenous nitric oxide and organic nitrates may be partly attributable to increased activity of type-5 phosphodiesterase in vascular smooth muscle.86,87 Specic inhibition of type-5 phosphodiesterase with sildenal acutely improves ow-mediated endothelium-dependent vasodilation in patients with CHF.88 No clinical trials of chronic type-5 phosphodiesterase inhibition therapy in CHF are yet available. MEASUREMENT OF SKELETAL MUSCLE BLOOD FLOW Because skeletal muscle blood ow is an important determinant of maximal exercise capacity and a potential therapeutic target, reliable measures of skeletal muscle blood ow during exercise have been the subject of numerous clinical investigations.89 Three methods for measuring skeletal muscle blood ow have been predominantly used in most clinical investigations. Venous occlusion plethysmography has been the most widely used, as this technique provides a noninvasive, technologically simple, and highly reproducible measure of forearm or calf blood ow. Venous occlusion plethysmography is not well suited to studies of exerciseinduced changes in limb ow, as measurements must be performed with the patient in the supine position after completion of exercise and are thus incompatible with the most common forms of treadmill and upright bicycle ergometry exercise testing. Dye dilution and thermodilution techniques have limited application in clinical investigations in CHF, as they require invasive catheterization of the femoral vein and/or artery and are not highly reproducible, especially in the case of CHF in which limb blood ows may be substantially lower than

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normal.89 The xenon 133 clearance technique is a variant on dye dilution and other injection indicator techniques that does not require invasive catheterization because it can be injected directly into muscle and its washout can be monitored noninvasively with an external counter. This is a promising technique, rst developed over 35 years ago, that has been underused in clinical studies of patients with CHF. It has potential advantages over other available techniques because it is only minimally invasive, requiring intramuscular injection with a smallgauge needle, and can measure skeletal muscle blood ow during normal maximal treadmill or bicycle exercise procedures.90 The low radiation energy of Xe-133 and its rapid elimination from the body via expiration minimize organ radiation exposure. The estimated gonadal radiation exposure after injection of Xe-133, 50 mCi, is 0.04 millirads.90 The details of this techniques methodology, uses, and limitations will be reviewed. The Xe-133 clearance method is based on the well-known Fick principle, which states that the rate of appearance (or disappearance) of a substance across a circulation of interest is determined by the blood ow through the circulation and the arteriovenous difference in the concentration of the substance.90 On the basis of early work by Kety91 and other authors, it was determined that inert gases such as xenon could be useful for measurement of organ blood ows, as these substances are highly diffusible in tissues and do not recirculate as a result of efcient removal from the lung circulation. In can be shown that when there is complete diffusion equilibrium of the tracer such that the concentration of the tracer in the organ is equal to the concentration in the blood, adjusted for a diffusion constant, then the ow through the organ will be determined (in milliliters per minute per 100 g of tissue) as follows: Flow S 1 1 ln(2)/T2 100, where S is the diffusion constant and T2 is the half-life of concentration of the tracer in the organ under study (derivation in Lassen et al90). For skeletal muscle the diffusion constant has been estimated to be 0.70.92,93 Accordingly, the mean skeletal muscle blood ow can be determined in milliliters per minute per 100 g of muscle tissue by the following equation: Mean skeletal muscle blood ow 161 D, where the half-time D can be determined from the slope of the semilogarithmic plots of counts from the injection site versus time.90,94 If the derived curves do not conform to a monoexponential model, a multiexponential analysis has also been proposed, although with somewhat divergent ndings reported. A stochastic model derived from an analysis of transit time of the tracer, in which mean blood ow is determined by the ratio of the peak height of the curve and its total area under the curve, has also been proposed.95,96 To measure skeletal muscle blood ow in human

subjects, Xe-133 (25-50 mCi) is dissolved in 0.1 to 0.3 mL of normal saline solution and injected with a smallgauge needle approximately 2-cm deep into the body of the muscle under study.77,90,94,97 The needle is left in place for 30 seconds to prevent escape of tracer from the needle entry site. The gamma emission of the isotope is registered continuously by a lightweight, portable cadmium telluride scintillation detector mounted with tape on the skin over the site of injection. Counts are accumulated by a personal computer in 2- to 5-second intervals and plotted semilogarithmically versus time after adjustment for background counts.98 The slope of the line from the semilogarithmic plot is used in the formula listed above. The Xe-133 clearance technique has been critically compared with other available techniques of skeletal muscle blood ow determination. In isolated feline and canine gastrocnemius and gracilis muscle preparations, blood ow determined by Xe-133 clearance was highly linearly associated with actual blood ow determined by venous collection or by microsphere techniques, although the slope of the regression line was less than 1, suggesting that the Xe-133 clearance technique was systematically underestimating the true muscle blood ow by approximately 30% to 50%.96,99-101 In these experimental preparations the stochastic method for calculation of ow yielded better estimates of true ow than the compartmental exponential analysis. Unfortunately, the stochastic method is more difcult to apply in clinical studies, as this analysis assumes a homogeneous muscle circulation such that the full height of the curve represents the total tracer input and the area under the curve is estimated to innity.96 The Xe-133 clearance technique has also been compared with venous occlusion plethysmography measurements in clinical studies of the lowerextremity circulation of healthy subjects and patients with occlusive arterial disease of the lower extremities.90,94,102-106 Unfortunately, the detailed methods for determination of ow by Xe-133 clearance were not provided in some of these studies. Gastrocnemius and anterior tibialis muscle blood ow determined from Xe-133 clearance was lower than calf blood ow determined by venous occlusion plethysmography in studies of healthy subjects. A similar discrepancy between Xe-133 derived ow in the gastrocnemius muscle and venous occlusion plethysmography in the calf was reported in subjects with occlusive vascular disease of the lower extremities. Several factors related to the assumptions inherent in the method, as well as practical application of the technique, may contribute to apparent underestimation of skeletal muscle blood ow by the Xe-133 clearance method. The diffusion constant for Xe-133, estimated to be 0.70, was derived from carefully performed in vitro

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and in vivo studies but has substantial variability, as it is inuenced by hematocrit and by nonmuscle tissue (fat and connective tissue) content in the muscle under study.96,99,101 Because human skeletal muscle may contain more fat stores than that of other species, some investigators have argued that the correct diffusion constant for human subjects is approximately 1.0. Adoption of a higher diffusion constant in the calculation would partially correct the reported underestimation of ow. The calculations of blood ow are based on the assumption of conditions of uniform distribution of tracer in a homogeneous tissue, which is unlikely to exist in human skeletal muscle. In addition to anatomic variations in fat, connective tissue, and skeletal muscle content at the site of tracer injection, blood ow within the skeletal muscle itself is not completely homogeneous but rather preferentially delivered to high oxidative muscle bers. In most studies of human subjects, fast and slow clearance rates consistent with nonhomogeneity have been described and ow has been calculated from a biexponential model, which may introduce additional error to the measurement.96,99,101 Although the volume of injection into muscle is small, some local tissue damage may also contribute to tissue heterogeneity. Xe-133 clearance may also be altered by venoarterial backdiffusion, which could create a microcirculation shunt and delay trace clearance, particularly at low ows.107 The direct comparison to plethysmography in clinical studies is limited because plethysmography measures entire limb arterial inow, which includes muscles in addition to the gastrocnemius and skin circulation.94,103 The Xe-133 clearance technique has been used in the investigation of skeletal muscle blood ow in healthy human beings and in patients with occlusive peripheral vascular disease. In healthy subjects blood ow to the vastus lateralis and anterior tibialis muscles was determined by the Xe-133 clearance technique during graded exercise.102,108-110 In all investigations skeletal muscle blood ow increased linearly at exercise levels up to 70% of maximum. In one study blood ow continued to increase up until maximal work rate, whereas in the other studies a plateau in skeletal muscle blood ow was observed at work rates above 70% of maximum. In all studies the maximum blood ow values measured by Xe-133 clearance were somewhat lower that those reported from other techniques. Measurement error was systematically evaluated in these studies with coefcients of variance ranging from 10% to 25%. The true skeletal muscle blood ow was likely underestimated in these studies, as the reported blood ows are too low to account for the rise in oxygen transport during lowerextremity exercise. One possible explanation for the underestimation, in addition to the methodologic issues discussed above, is that skeletal muscle perfusion of

supercial muscles as a proportion of total muscle blood ow decreases at near-maximal exercise work rates. In patients with occlusive arterial disease, Xe-133 clearance skeletal muscle blood ow is decreased to values that are less than 50% of those observed in healthy subjects in a manner that corresponds to the severity of the anatomic disease.90,94,104,105 Although the procedure was well tolerated in reported studies, Xe-133 clearance is not routinely used in clinical evaluation of patients with lower-extremity occlusive vascular disease. Although the Xe-133 clearance technique appears to underestimate actual skeletal muscle blood ow, it may be useful in clinical studies in which change in skeletal muscle perfusion is the primary endpoint of interest. In this setting the only limitation of the technique is its relatively large coefcient of variance, which would necessitate larger study populations for a given power to detect clinically relevant differences among treatment groups. The Xe-133 clearance technique has been used to assess comparative exercise hyperemia in the anterior tibialis muscle during graded bicycle ergometry in healthy subjects and patients with CHF.97 In accord with previous publications that used other techniques, skeletal muscle blood ow during exercise was decreased in patients with CHF when compared with healthy subjects and was correlated to exercise capacity (r 0.54, P .01). The Xe-133 clearance technique for measurement of skeletal muscle blood ow was also used in a landmark study by Mancini et al77 that investigated the effects of chronic ACE inhibition with captopril on exercise capacity in 8 patients with CHF. Because of the small study population size, mean skeletal muscle blood ow did not increase signicantly from baseline in the study population after captopril treatment. However, skeletal muscle blood ow was noted to increase substantially in 4 patients, with improvement in functional capacity as determined by peak oxygen uptake. A close association between increase in peak aerobic capacity and peak skeletal muscle blood ow was observed (Figure 4). This nding, which was subsequently conrmed in a placebo-controlled study, is consistent with the above discussion of the potential of skeletal muscle perfusion as a target for therapeutic interventions in patients with CHF.111 Skeletal muscle perfusion may also be assessed with positron emission tomography (PET) with O-15labeled water.112 The technique in skeletal muscle is adapted from PET methods for blood ow determination in brain and cardiac muscle.112,113 For quantitative measurements, an arterial line is required for blood sampling to determine the input function. PET is the only available technique that can provide quantitative regional blood ow information within individual skeletal muscles of the exercising limb.114 PET is also the only method to

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CONCLUSIONS Exercise intolerance in patients with CHF is related to chronic changes in structure and function of the heart and vessels, which lead to reduction of cardiac output reserve and hypoperfusion of skeletal muscle during exercise. Chronic neurohormonal activation, endothelial dysfunction, and deconditioning may contribute to the abnormalities of skeletal muscle blood ow, function, and metabolism in patients with CHF. A combination of pharmacologic (neurohormonal blockade) and nonpharmacologic therapy (physical training) may provide the optimal regimen to improve functional capacity in patients with CHF. Therapies that increase skeletal muscle perfusion are associated with concomitant increases in peak aerobic capacity. The Xe-133 clearance method for measurement of skeletal muscle blood ow is the only noninvasive technique that allows measurement of blood ow during maximal treadmill or bicycle exercise. If skeletal muscle blood ow measurements are performed in accordance with the fundamental principles of the technique, with recognition of the method limitations and appropriate controls for sources of experimental error, the Xe-133 technique appears to be a useful tool for measurement of skeletal muscle blood ow in clinical investigations. Measurement of skeletal muscle blood ow with PET and O-15labeled water is a promising tool for investigation of heterogeneity of blood ow within the skeletal muscle circulation, although the need for arterial blood sampling limits its application for serial measurements in response to therapy. Acknowledgment
The authors have indicated they have no nancial conicts of interest.

Figure 4. A plot of change in peak oxygen uptake versus change in skeletal muscle blood ow in response to chronic captopril therapy in 8 patients with CHF. Improvement in peak oxygen uptake was closely associated with increased skeletal muscle blood ow as determined by the Xe-133 clearance technique. (Used with permission from Mancini et al. J Am Coll Cardiol 1987;10:845-50.)

provide quantitative information on heterogeneity of skeletal muscle blood ow, which may be related to endothelial function in the skeletal muscle microcirculation.115-117 Blood ow determinations by PET and venous occlusion plethysmography in healthy subjects are in a similar range when expressed as ow per unit of tissue but are only moderately correlated, likely because PET strictly measures skeletal muscle ow whereas venous occlusion plethysmography measures total limb ow (including skin circulation).113 PET has been used to measure blood ow during repetitive plantar exion exercise in the lower extremity of healthy subjects and patients with peripheral vascular disease but has not been used in studies in patients with CHF.118 Because a better understanding of regional distribution and heterogeneity of skeletal muscle blood ow in response to exercise in CHF is needed, PET would appear to be a promising technique for application in clinical CHF studies. Its use is limited by the need to have the limb under study immobilized to avoid motion artifact and the requirement for arterial blood sampling for quantitative measurements.

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