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1868 Editorial Comment Reduced Aerobic Enzyme Activity in Skeletal Muscles of Patients With Heart Failure A Primary Defect or a Result of Limited Cardiac Output? Karlman Wasserman, MD Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017 Anumber of important contributions to the pathophysiology of heart failure have come from the exercise laboratory at Duke University. In their most recent report, which appears in this issue of Circulation, Sullivan et al1 report that skeletal muscle oxidative enzyme activity is reduced in heart failure and attribute parts of the increased anaerobiosis and lactate production at low work rates observed in these patients to this mechanism. They suggest that the reduction in enzyme activity contributes to the reduced exercise capacity and lactic acidosis in heart failure. But is the reduction in aerobic enzyme activity in the skeletal muscle a primary disturbance accompanying heart failure, which adds to exercise limitation, or simply atrophy of skeletal muscle, which accompanies decreased exercise tolerance without contributing to it? See p 1597 These investigators also examined skeletal muscle phosphocreatine decrease and lactate increase as potential mechanisms of fatigue. They concluded that neither could account for fatigue. But one important function in the fatigue mechanism, which was not measured, is the rate of aerobic regeneration of high energy phosphate (ATP). This factor is reflected in the rate of Vo2 increase in response to the work rate stimulus. To what degree does heart failure impair oxygen supply to the muscles, thereby limiting the rate of ATP regeneration from aerobic metabolism? An inadequate rate of increase in oxygen supply forces more energy to be derived from anaerobic mechanisms, or, if the latter is inadequate, fatigue must occur. When addressing exercise fatigue and adaptive mechanisms in heart failure, limited perspective is gained by measuring only some comThe opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, Torrance, Calif. Address for correspondence: Karlman Wasserman, MD, Department of Medicine, Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509. ponents in the bioenergetic process. The oxygen supply-demand balance must be considered. Changing Rate of Oxygen Consumption in Response to Constant Work Load Exercise and Fatigue At the highest work rate performed by the heart failure patients of Sullivan et al,' the Vo2 was unexpectedly low. It can be calculated from either total body Vo2 or by oxygen consumption calculated from leg blood flow and arteriovenous oxygen difference, that the exercising muscles of the heart failure group had an oxygen consumption of only about 70% of normal at the submaximal cycle ergometer work of 300 kpm/min. Aerobic ATP regeneration therefore was taking place at only about 70% of the normal rate. Patients with heart failure do not have increased bioenergetic efficiency. Therefore, the failure of these patients to increase Vo2 appropriately, in response to the work load, may reflect inability of their circulation to transport oxygen fast enough to regenerate the ATP required, that is, oxygen supplydemand imbalance. An oxygen supply inadequate to regenerate ATP aerobically may cause a delay in Vo2 steady-state time.2 Vo2 reaches a steady-state by 3 minutes when performing constant exercise without a lactic acidoSiS.3 The slow rate of rise in Vo2 after 3 minutes that accompanies lactic acidosis might result from muscle hypoxia-stimulated vasodilating agents and lactic acidosis acting to shift the oxygen dissociation curve to the right, thereby facilitating unloading of oxygen from hemoglobin. Since the work duration for each level of work performed by the heart failure and normal subjects was 3 minutes in Sullivan et al's study,' the reduced Vo2 in the heart failure subjects could be interpreted as an increased oxygen deficit and failure to reach steady-state aerobic ATP regeneration. This mechanism is likely a major contributing factor to exercise fatigue in heart failure. Additional factors that may play a role in the fatigue mechanism are the H' buffering capacity and volume changes of the exercising muscle cells. Muscle cell pH is about 7.0.4 Thus, the bicarbonate concentration in these cells can be estimated to be Wasserman Reduced Aerobic Enzyme Activity in Skeletal Muscles about 12 meq/l. Experimental data support that HCO3 is the major intracellular buffer of lactic acid.5 Since HCO3 is volatile, minimal change in pH results when HCO3 takes up the H' of lactic acid Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017 and leaves the cell as CO2. But nonvolatile buffers must take up H' when intracellular lactate increases sufficiently to exhaust the volatile HCO3 buffer. The pH decrease must then accelerate. But also intracellular osmolality should increase when lactate accumulates without a simultaneous loss of an intracellular anion. Thus, both cell swelling and rapidly decreasing cell pH might contribute to muscle fatigue. The reduced work capacity and peak lactate at the point of fatigue in normal subjects exercising at high altitude6 may be explained in part by oxygen supply-demand imbalance and the reduced blood and therefore cell HCO3 concentration found in high-altitude acclimatized subjects. Thus, it might be predicted that lactate could not increase much beyond the buffering capacity of the volatile HCO3 buffer. In support of increased lactic acid as a mechanism of fatigue, Sahlin7 postulated that the intracellular acidosis accompanying the increase in lactate may block excitation-contraction coupling by inhibiting the rephosphorylation of cytosolic ADP. In further support is the observation that endurance time decreases the higher the lactate concentration.8 Fatigue can be viewed as a condition in which the sum of the rates of aerobic metabolism, reflected by Vo2, and anaerobic metabolism, reflected by the rate of lactate increase, cannot meet the rate of ATP regeneration required by muscles to sustain work. The increase in blood lactate during exercise is correlated with the degree of slowing of oxygen uptake kinetics.9 That the total energetic requirement is not being met by aerobic plus anaerobic mechanisms is suggested by the failure of Vo2 and lactate to reach steady states. Aerobic mechanisms allow for continual regeneration of energy during sustained exercise, without disturbing the internal environment, except for a gradual reduction in energy substrate. The amount of energy that can be generated by anaerobic mechanisms is small. The oxygen stores (oxyhemoglobin and oxymyoglobin) and the anaerobic mechanisms (splitting of phosphocreatine and reoxidation of cytosolic NADH by pyruvate to form lactate) are quantitatively limited, being equal to no more than several liters of oxygen. Sullivan et all concluded that neither increase in lactate nor decrease in phosphocreatine could totally account for the fatigue of their patients because neither changed as much in the patients as in the normal subjects at their respective maximal work rates. However, it is clear from their data that lactate increased and phosphocreatine decreased more rapidly in the patients than the normal subjects when related to work rate. While different mechanisms could have contributed to the fatigue of the patient and normal groups, reduced aerobic ATP regenera- 1869 tion was likely the major factor contributing to the fatigue in the heart failure patients. Decreased Skeletal Muscle Aerobic Enzyme Activity in Heart Failure: A Primary Maladaptation Reducing Exercise Performance or a Response to Inactivity? The peripheral circulation is controlled by local factors that optimize matching of blood flow to the tissue metabolic rate. This matching accounts for the uniformity in the Vo2 cardiac output relation in normal trained and sedentary subjects.'0 However, patients with heart failure may not transport adequate oxygen to skeletal muscle during exercise. Because a partial pressure gradient is needed for diffusion of oxygen from blood to mitochondria, oxygen extraction cannot be total. Since 5 1 of blood contain only 1 1 of oxygen, when the hemoglobin concentration is normal and maximally saturated with oxygen, it is clear that an excess of 5 1 of blood per minute must be delivered to the exercising muscles to perform work requiring 1 1 of oxygen per minute. While the lowest end-capillary Po2 that can be achieved during exercise without anaerobiosis is unknown, the micro Po2 electrode studies of BylundFellenius et all' suggest that it must exceed 8-10 mm Hg. Heart failure limiting oxygen transport to muscles would obligate the patient to a reduced maximal oxygen consumption, reducing the needed level of muscle aerobic enzymes. Thus, the reduction in mitochondrial oxidative enzymes found in heart failure patients might represent matching to the decreased oxygen transport, that is, atrophy of the muscle aerobic energy-generating mechanism due to symptom-enforced inactivity.' Sullivan et all suggest that reduced aerobic enzyme activity is mechanistically important in mediating the reduction in maximal oxygen uptake and increased anaerobic metabolism at low work rates in their heart failure patients. If true, this must be considered to be a maladaptation of the metabolic processes, which worsens exercise tolerance beyond that dictated by the cardiac lesion. But their study did not differentiate between a deficiency in aerobic enzyme activity and inadequate oxygen transport (cardiac output) as the cause of the reduced peak Vo2 performed by their patients. If the cardiac output increase is limited, then the transport of oxygen to the tissues is limited and the maximal Vo2 would be reduced. Thus a reduced ability to increase cardiac output and oxygen transport might result in a pari passu decrease in the concentration of enzymes that catalyze the aerobic-energygenerating mechanisms. Relevant to the question of whether a shortage of aerobic enzymes or oxygen transport determines the work capacity in normal subjects are the studies on maximal one- and two-legged exercise reported by Davies and Sargeant.'2 They provide evidence that the muscle aerobic enzyme activity exceeds that required to perform cycle ergometer exercise so that 1870 Circulation Vol 84, No 4 October 1991 Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017 the maximal VoJkg for one-legged exercise was more than one half of that for two-legged cycle exercise. Similarly, in studies on oxygen uptake and blood flow of the knee extensor muscles of one leg during maximal knee extension exercise, Anderson and Saltin13 found that the maximal blood flow and oxygen uptake per kilogram of the active muscle was considerably higher than would be present if larger muscle groups were simultaneously active. They concluded that when a large fraction of the muscle mass is actively engaged in exercise, the capacity of the skeletal muscles to consume oxygen exceeds the capacity of the central circulation to supply it with blood and oxygen. Similarly, one- and two-legged exercise might be studied in heart failure patients to discriminate between aerobic enzyme and muscle blood flow limitations. If the patient's reduced Vo2 max resulted from reduced aerobic enzyme activity, then the increase in Vo2 for maximal one-legged exercise should be one half of that for two-legged exercise. However, if oxygen flow were limiting, the increase in maximal Vo2 for one-legged exercise should be more than one half of the Vo2 increase for two-legged exercise. That the muscles adapt to the aerobic capacity of the subject may be an important concept to keep in mind when evaluating the benefits of pharmacological therapy in chronic heart failure patients. Exercise capacity would not be expected to improve to any great degree immediately, even with successful heart failure therapy, because of the chronic atrophic changes in muscle induced by inactivity. Thus to determine the true benefits of treatment, training may be required to regenerate aerobic enzymes to match the patient's improved cardiovascular function. If the cardiovascular transport of oxygen in support of muscle aerobic metabolism improves, it would be seen more quickly if the skeletal muscle aerobic capacity were simultaneously stimulated to accounting for reduced aerobic enzymes in the skeletal muscle of heart failure patients, similar to that found in normal subjects undergoing experimental detraining,14 is perhaps a more reasonable explanation than a coexisting primary skeletal muscle disturbance, acting to impair the patient beyond that caused by their reduced cardiac function. References 1. Sullivan MJ, Green HJ, Cobb FR: Altered skeletal muscle metabolic response to exercise in chronic heart failure: Relationship to skeletal muscle aerobic enzyme activity. Circulation 1991;84:1597-1607 2. Wasserman K: New concepts in assessing cardiovascular function. Circulation 1988;78:1060-1071 3. Whipp BJ, Wasserman K: Oxygen uptake kinetics for various intensities of constant load work. J Appl Physiol 1972;33: 351-356 4. Wilson JR, McCully KK, Mancini DM, Boden B, Chance B: Relationship of muscular fatigue to pH and diprotonated Pi in humans: A31P-NMR study. JAppl Physiol 1988;65:2333-2339 5. Beaver WL, Wasserman K, Whipp BJ: Bicarbonate buffering of acid generated during exercise. J Appl Physiol 1986;60: 472-478 6. Edwards HT: Lactic acid in rest and work at high altitudes. Am IPhysiol 1936;116:367-375 7. Sahlin K: Muscle fatigue and lactic acid accumulation. Acta Physiol Scand 1986;128(suppl 556):83-91 8. Wasserman K: The anaerobic threshold measurement to evaluate exercise performance. Am Rev Respir Dis 1984;1 16: 367-375 9. Roston WL, Whipp BJ, Davis JA, Effros RM, Wasserman K: Oxygen uptake and lactate kinetics during exercise in man.Am Rev Respir Dis 1987;135:1080-1084 10. Rowell LB: Human Circulation Regulation During Physical Stress. New York, Oxford University Press, Inc, 1986, p 215 11. Bylund-Fellenius AC, Walker PM, Elander A, Holm S, Holm J, Schersten T: Energy metabolism in relation to oxygen partial pressure in human skeletal muscle during exercise. Biochem J 1981;200:247-255 increase. The concept of a primary aerobic enzyme deficiency limiting exercise capacity in heart failure appears to 12. Davies CTM, Sargeant AJ: Physiological responses to one and two leg exercise breathing air and 45% oxygen. JAppl Physiol 1974;36:142-148 13. Anderson P, Saltin B: Maximum perfusion of skeletal muscle in man. JAppl Physiol 1985;366:233-249 14. Saltin B, Gollnick PD: Skeletal muscle adaptability: Significance for metabolism and performance, in Handbook of Skeletal Muscle. Bethesda, Md, American Physiological Society, 1988, pp 589-596 denigrate the importance of the underlying defect in heart failure patients. Rather, enforced detraining KEY WORDS * heart failure * exercise * Editorial Comments Reduced aerobic enzyme activity in skeletal muscles of patients with heart failure. A primary defect or a result of limited cardiac output? K Wasserman Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017 Circulation. 1991;84:1868-1870 doi: 10.1161/01.CIR.84.4.1868 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1991 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/84/4/1868.citation Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/