Reduced exercise capacity is the main complaint of patients with chronic congestive heart failure (CHF). However, the best method to measure it is still controversial. In these past decades, the introduction of devices that can measure breath by breath respiratory gas analysis has radically improved our ability to gauge functional capacity. Peak VO2, obtained using maximal exercise testing, has become one of the most important parameters for assessment of both the prognosis and the effects of therapy in patients with CHF. However, the variables measured by maximal exercise testing are poorly related to everyday physical activity, which is characterized by the performance of a series of submaximal tasks. Therefore, these variables are relatively insensitive for evaluation of the effects of therapy. For this reason, different kinds of submaximal exercise testing are more and more frequently used. However, no standard method to assess submaximal functional capacity is now available and, moreover, many of the procedures proposed rely on performance of an exercise leading to exhaustion, which therefore has characteristics similar to the ones of a maximal exercise test.
WHY SHOULD WE USE EXERCISE TESTING IN PATIENTS WITH CHRONIC HEART FAILURE?
Functional capacity vs. left ventricular function and clinical assessment
The need to directly assess functional capacity derives both from its lack of relationship with resting left ventricular (LV) function and from the low accuracy of the classifications merely based on clinical evaluation.
Many studies have shown that functional capacity is poorly related to measures of resting LV function (1-11)(Fig. 1). Furthermore, the hemodynamic changes induced by therapy are not predictive of functional capacity, so that an agent may induce a significant acute and chronic hemodynamic improvement with no change in functional capacity (12-15).
This lack of correlation may seem paradoxical at first, because it is unquestionable that myocardial damage is always the initial cause of the clinical picture of CHF. However, many factors link myocardial dysfunction to the patient symptoms (Table 1) so that, finally, resting LV dysfunction becomes poorly related to functional capacity. Accordingly, up to 25% of patients with CHF and significant functional limitation may exhibit normal skeletal muscle blood flow during exercise, with increased lactic acid production caused only by metabolic abnormalities of the skeletal muscle (31). Therefore, a simple assessment of resting LV function does not enable prediction of either the cardiac output response to exercise or the maximal functional capacity. This latter variable must be assessed directly in patients with CHF.
Functional capacity can be gauged either by a clinical evaluation of the patient symptoms or by specific procedures such as exercise testing. Classifications based on clinical evaluation, like that of the New York Heart Association, have an accuracy that is too low for assessment of functional capacity. They are, in fact, highly dependent on subjective issues related to how the patient perceives and describes the symptoms and to how they are interpreted by the physician. Therefore, although the clinical tools can easily identify extreme situations, e.g., patients who are symptomatic at rest or those who are completely asymptomatic, they fail to quantify the different degrees of functional limitation in patients who are symptomatic only during effort, who comprise the vast majority of ambulatory patients with CHF (32-34). Direct assessment of functional capacity through exercise testing is therefore mandatory in these patients.
MAXIMAL EXERCISE TESTING: NONRESPIRATORY PARAMETERS
A maximal exercise test is one that is performed with progressively increasing workloads up to limiting fatigue and/or dyspnea caused by exhaustion of the capacity for adaptation of the patient's cardiovascular system.
Traditional exercise testing, e.g., without respiratory gas monitoring, yields parameters that can be used as indices of functional capacity, such as peak exercise duration and peak exercise workload. These variables have been widely used in multicenter trials because they can be obtained rather easily and inexpensively.
Peak exercise duration and workload may be sensitive enough to detect the changes in functional capacity induced by therapy when relatively large study groups are evaluated. However, they are not suitable for assessment of single patients or small study groups because of their relative inaccuracy and low reproducibility.
Peak VO2 cannot be reliably predicted on the basis of the peak workload in patients with CHF (Fig. 2). In fact, the relation between the workload performed and the VO2 tends to decrease as patients with more severe functional limitation are considered (34,35). Moreover, many other factors, such as bicycle ergometer calibration, variations in the speed of pedaling, or variations in the strength with which the patient keeps himself tightened to the handrails, influence it. Therefore, direct assessment of VO2 during exercise allows a more accurate evaluation of the work performed by the patient. Second, respiratory gas monitoring with detection of the anaerobic threshold ensures that exercise is interrupted because of exhaustion of the capacity of the cardiovascular system with relative skeletal muscle hypoperfusion and lactic acidosis. In contrast, the interruption of exercise testing without respiratory gas monitoring may be influenced by subjective factors such as the patient's motivation, the physician's incitement to continue the exercise, and clinical evaluation of the patient's symptoms.
Maximal VO2 and peak VO2
Maximal VO2 is defined as the value of VO2 at which this variable remains stable, reaching a plateau, despite an increase in the workload, in incremental exercise testing (34,36-38). VO2 represents the maximal amount of oxygen a subject can utilize during physical activity and therefore measures both the maximal capacity of oxygen distribution by the cardiovascular system and that of oxygen uptake by the peripheral tissues.
When assessed in normal subjects, maximal VO2 is an objective and reproducible measure of maximal functional capacity. However, a clear-cut plateau of VO2 at peak exercise can be observed only rarely in patients with CHF because they are unable to sustain a maximal effort for more than a few seconds (10,34,36,39). In these patients we measure peak VO2, which is generally defined as the VO2 measured during the last 30 s of maximal exercise.
The lack of a VO2 plateau during exercise significantly reduces the reliability and objectivity of this variable because it may be influenced by the patient's motivation. However, when the anaerobic threshold is observed, this ensures that a maximal task has been performed and, accordingly, the reproducibility of peak VO2 was greater than the one of other variables in many studies (36,39,40). A derived parameter, the extrapolated maximal VO2, is less dependent on the patient's motivation(41).
In a normal subject, VO2 at peak exercise may reach values 10 to 20 times higher than those at rest. This is obtained through a four- to fivefold increase in the cardiac output, with a concomitant two- to threefold increase in the peripheral arteriovenous oxygen difference (37,38). Heart failure is characterized by impairment of the exercise-induced increase in cardiac output, and therefore peak VO2 and functional capacity are also reduced. Accordingly, peak VO2 is closely related to peak exercise cardiac output (Fig. 1), whereas its correlation with right and left ventricular filling pressures is much smaller (3-11). Quantification of the severity of CHF on the basis of peak VO2(3), in addition to the clinical classification of the New York Heart Association, has become very popular.
It is now common clinical practice to correct peak VO2 only for body weight (3). However, age, sex, and body composition, in addition to body weight, may also influence VO2 in patients with CHF (42,43). It may therefore be better to express peak VO2 as a percentage of the maximal predicted values rather than correcting only for body weight (34-36). This method has yielded a greater prognostic accuracy in some study groups (44,45).
Peak VO2 has been shown to be one of the main independent prognostic variables in patients with CHF (44-47). It is now regarded as the most important parameter for selection of patients for heart transplantation (48). However, the use of only a peak VO2 ≤14 ml/kg/min as a major criterion for heart transplantation may sometimes be misleading (49). In fact, as already stated, peak VO2 is influenced by many factors in addition to the cardiac response to exercise. These include the patient's age (Fig. 3) and sex, whose influence may be eliminated by expressing peak VO2 as a percentage of the maximal predicted values (44,45). In addition, a low peak VO2 may also be mainly caused by skeletal muscle deconditioning in up to about 25% of ambulatory patients with CHF (31). Such patients can be identified only through additional procedures, such as cardiopulmonary exercise testing with concomitant hemodynamic monitoring (50,51) and/or repetition of noninvasive exercise testing after 3-6 months (52). Patients whose main reason for a low exercise capacity is skeletal muscle deconditioning will have a normal cardiac output response to exercise (50,51) and an improvement of functional capacity during follow-up (52).
Peak VO2 is now the main variable used to assess the effects of therapy on functional capacity. In the VHe-FT trials peak VO2 has been serially assessed for more than 1 year in a large group of patients (53). These trials show how the clinical course of CHF is characterized by a progressive decline in both LV function and maximal functional capacity, in agreement with the poor prognosis for these patients (53). However, a dissociation between the effects of therapy on mortality and functional capacity may be observed, because enalapril was more effective on prognosis, whereas only the hydralazine isosorbide dinitrate combination was able to significantly improve peak VO2 in the VHeFT-II trial (53). These data show the utility of cardiopulmonary exercise testing for assessment of the clinical course of CHF.
Peak VO2 has some important limitations in the evaluation of the effects of therapy. First, it is a measure of maximal functional capacity. However, even if it may have an important prognostic value it bears only a slight relationship to everyday physical activity when the patient performs a series of submaximal, brief physical tasks. Accordingly, it is often poorly related to measurements regarding daily physical activity and quality of life (54,55). Despite its high reproducibility, peak VO2 has low sensitivity for detection of the effects of therapy, and the clinical significance of the changes observed may be slight. In the majority of studies, changes in peak VO2 approximate 1-2 ml/kg/min. It is difficult to believe that such changes have any clinical relevance in patients with CHF. The relatively low sensitivity of peak VO2 to drug-induced changes may be explained by the many factors that may influence it (Table 1). For example, drugs that can improve LV function and hemodynamics are unable to alter functional capacity in patients with CHF in whom skeletal muscle deconditioning is the main cause of reduced functional capacity (31). These patients have been shown to be especially sensitive to the effects of physical training (56).
The anaerobic threshold
Many of the shortcomings of peak VO2 can also pertain to the anaerobic threshold. The anaerobic threshold corresponds to the work rate at which oxygen delivery to the tissues becomes inadequate and anaerobic glycolysis becomes the main source of energy production (38,57). It can be measured during incremental exercise testing both invasively, as the point at which arterial or mixed venous lactate levels start to increase more steeply, or noninvasively, through respiratory gas monitoring, as the point at which carbon dioxide production (VCO2) and minute ventilation (VE) start to increase more than VO2(3,10,38,39,40,57-59). These respiratory changes occur because the increase in lactic acid production by the skeletal muscle is buffered by the bicarbonate/carbonic acid system, with a secondary increase of CO2 that stimulates ventilation. The use of the V-slope method, based on the detection of the change of the slope of the relation between VO2 and VCO2, allows detection of the anaerobic threshold in a larger number of patients with greater reproducibility (59). The anaerobic threshold has shown relatively low interobserver variability and relatively good reproducibility, when measured after either days (10,40) or months (60) in patients with CHF.
The anaerobic threshold corresponds to the work rate that the patient can maintain for a prolonged period of time without lactic acidosis and sensations of fatigue (57). Patients with CHF exhibit a reduction in the anaerobic threshold which, similar to peak VO2, can be used as an index of disease severity (3,10,34,57). The anaerobic threshold and peak VO2 are closely linked to each other, with the former occurring at about 60-70% of peak exercise (10,34). The same hemodynamic variables that determine peak VO2 are also related to the anaerobic threshold (10).
Compared with peak VO2, the anaerobic threshold has the potential advantage of not requiring performance of a maximal test, and is therefore less dependent on patient motivation. It has been often used as a measure of the changes in functional capacity induced by therapy(12,13,53,61-63) or physical training(64). In some studies it has been more sensitive than peak VO2(62) although, as already stated, it has a similar clinical significance.
The physiopathologic significance of the anerobic threshold has been widely discussed. It has been pointed out that lactic acid production by fast-twitch skeletal muscle fibers may be present even at rest or at low workloads, and that the increase in lactic acid at peak exercise may be caused by a decline in hepatic blood flow and lactic acid metabolism rather than by its increased production (65,66). However, nuclear magnetic spectroscopy studies have demonstrated a progressive skeletal muscle acidosis induced by exercise with an earlier occurrence in patients with CHF compared to normal subjects (67,68). These changes represent the physiopathologic basis of the anaerobic threshold. Interestingly, they may also occur in the presence of a normal peripheral blood flow (67,68).
The main shortcomings of the anaerobic threshold are probably related to its clinical application rather to its physiopathologic significance. First, despite the improvements obtained with the V-slope method (59), the anerobic threshold cannot be detected in up to about 25% of ambulatory patients with CHF (10,39,58,61). This percentage may even increase when patients with a more severe limitation of functional capacity are considered (69). These difficulties of determination may be caused by oscillations of the respiratory variables during exercise and/or by the occurrence of lactic acid production even at low levels of exercise in patients with more severe peripheral hypoperfusion. Because of these difficulties of detection, the anaerobic threshold may have a relatively low sensitivity in the assessment of changes induced by therapy. For example, it has been calculated that, to be significant on an individual basis, the change in the VO2 at the anaerobic threshold must be ≥3.3 ml/kg/min (i.e., twice the standard error of its spontaneous variations)(58). Such changes occur very rarely in CHF trials.
Because of these shortcomings, the anerobic threshold is less useful than peak exercise duration and, above all, peak VO2 in the assessment of the effects of therapy on maximal functional capacity (53,61). Changes in peak VO2 therefore cannot be used as a primary end point of therapy. Rather, the usefulness of peak VO2 appears to be mainly indirect. Detection of the anerobic threshold is an index that exercise testing has been maximal and has been interrupted because of exhaustion of the cardiovascular reserve with skeletal muscle hypoperfusion and metabolic acidosis. Detection of the anerobic threshold allows exclusion of the possibility that exercise has been terminated because of poor patient motivation, peripheral artery disease with leg pain, or pulmonary disease.
The ventilatory response to exercise
Compared to normal subjects, patients with CHF exhibit an increase of minute ventilation at matched workloads (3,25,29,30,70,71). The ventilatory response to exercise should be measured relatively to some of its main determinants, e.g., VCO2, rather than as an absolute value (29,30,71). The slope of the VE vs. VCO2 relation is significantly increased in patients with CHF compared to normal subjects (29,30,71). It is inversely related to exercise duration, peak VO2, and the anaerobic threshold (70). Because it requires performance of an effort carried out up to above the anerobic threshold, it must be considered as a parameter of maximal effort.
Exercise hyperpnea may be a factor contributing to the reduction of functional capacity of patients with CHF. In fact, it increases the work of the respiratory muscles, a mechanism which, with the concomitant reduction of the cardiac output, may cause respiratory muscle deoxygenation and the sensation of dyspnea (72). Many interventions, including administration of ACE inhibitors, physical training, and heart transplantation, have been shown to reduce the ventilatory response to exercise(71). It has also been shown that measurement of the ventilatory response to exercise may further improve the prognostic assessment of patients with CHF compared to peak VO2(73).
The mechanisms of the increased ventilatory response to exercise are multiple. Below the anerobic threshold, an important factor is represented by the increase in the ratio of pulmonary dead space to tidal volume consequent to the reduction in pulmonary perfusion and the increased ventilation-perfusion mismatch. The increased ventilatory response to exercise can therefore be considered a compensatory mechanism, controlled by arterial chemoreceptors and aimed to maintain constancy of the arterial blood gases despite the increase in the functional dead space (30). However, compared to those with a normal ventilatory response, patients with more severe exercise hyperpnea exhibit no major changes in arterial PaO2 and pH, with a greater decline in PaCO2 and a lower reduction in arterial bicarbonate at the end of exercise(30). This shows that additional mechanisms stimulate the ventilatory response to exercise and tend to mask the metabolic acidosis that occurs at the end of exercise. These mechanisms include an increased sensitivity of the arterial chemoreceptors(74) and reflexes driven by metaboreceptors and mechanoreceptors of the abnormal skeletal muscles (25).
PARAMETERS AT THE START AND END OF EXERCISE: RELATED TO EVERYDAY LIFE?
Patients do not perform maximal tasks during everyday life. Their activity is instead characterized by many submaximal efforts of short duration, and the main source of their symptoms may be represented by the oxygen debt they gain at the start of each exercise when the cardiorespiratory system must adapt itself to the increased workload. Therefore, assessment of the cardiorespiratory response at the start and at the end of exercise might furnish significant information related to patient symptoms and quality of life.
In normal subjects, the VO2 increment at the start of exercise has two phases: a first phase characterized by a rapid increase, lasting about 15 s, during which VO2 can double its resting values, followed by a second phase lasting less than 2-3 min, during which VO2 increases exponentially up to a steady state when the VO2 required by the workload is reached (38). When the work rate used is above the anaerobic threshold, VO2 does not reach a steady state but continues to increase slowly beyond the first 3 min (75,76). The oxygen deficit gained at the start of exercise is then paid back at its end by an increase in VO2 above the resting values (oxygen debt)(38).
The kinetics of VO2 both at the start (77,78) and at the end of exercise (79-81) are delayed in patients with CHF compared to normal subjects. Indices of VO2 recovery appear to be independent of the workload used (80) and to be applicable with protocols based either on constant workloads or on incremental maximal exercises (80,81). The half-time and the time constant of VO2 recovery (80,81) and the ratio between total VO2 during exercise and during recovery (81) have been found to be related to peak VO2(80,81) and may have an independent prognostic value in patients with a moderate degree of functional limitation (maximal predicted VO2 >40%) (81). These parameters present many potential advantages in comparison to peak VO2 and the anerobic threshold. They can also be obtained using submaximal protocols, e.g., with exercises interrupted before the anaerobic threshold is reached. They are therefore independent of the patient's motivation, and are objective and reproducible(80). They also appear to be more closely related to the symptoms of the patients, because they are mainly involved in many brief, submaximal exercises and most of their symptoms may be caused by the delayed adaptation of the cardiorespiratory system to the workload performed. However, no index of VO2 kinetics has been widely used and validated up until now, and no data are available regarding their relation to patients' symptoms and quality of life and their sensitivity to the effects of therapy.
SUBMAXIMAL EXERCISE DURATION, 6-MIN WALK TEST, AND 9-MIN TREADMILL TEST: PARAMETERS OF SUBMAXIMAL OR MAXIMAL EXERCISE?
After having been used by physiologists for a long time, protocols based on constant workloads have also been proposed for evaluation of patients with CHF. In these protocols the duration of an exercise performed at a constant work rate is measured. Because these protocols utilize a submaximal workload, they appear to more accurately reproduce everyday activity when the patient walks or rides a bicycle.
Protocols based on the measurement of submaximal exercise duration are critically dependent on the workload used. When it is below the anerobic threshold, exercise may be pursued for a very long time, beyond 20-30 min. Therefore, if these examinations are used to quantify changes in functional capacity, the workload of the baseline test should probably be just above the anaerobic threshold, i.e., at about 80% of the maximal workload; so that the exercise will be maintained only for a few minutes. If the patient then improves in functional capacity during follow-up, the work rate used in the first examination will now be below the anaerobic threshold and so the exercise duration will be longer. This kind of protocol is therefore able to magnify changes related to variables in maximal functional capacity, e.g., the anaerobic threshold, but, at the same time, is less dependent on parameters, such as maximal heart rate, that influence peak VO2.
These characteristics explain why this protocol has been able to demonstrate the improvement in functional capacity induced by chronic administration of carvedilol, a nonselective β-blocker with associated α-antagonist, antiproliferative and antioxidant activities. In a placebo-controlled trial in patients with idiopathic dilated cardiomyopathy, this agent did not change peak VO2 and VO2 at the anerobic threshold despite a highly significant improvement in LV function and stroke volume both at rest and during exercise (82). In fact, the marked reduction in peak exercise heart rate caused by β-blockade hindered the improvement in peak exercise cardiac output that would have been necessary to also change the peak VO2. In contrast, submaximal exercise duration, which is less dependent on peak exercise heart rate, exhibited a significant increase that was related to the improvement in the New York Heart Association functional class and quality of life, as assessed through the Minnesota Living with Heart Failure questionnaire (82,83). Protocols based on an exercise at a constant work rate have also been able to show a significant improvement after physical training (84).
Assessment of submaximal exercise duration has not been sensitive enough to detect the changes induced by therapy in multicenter studies (53). It is probable that these unsatisfactory results are at least partially caused by the baseline workload used which, in some cases, may have been too low. Accordingly, 185/370 studies (50%) were excluded from data analysis because of a baseline exercise duration >18 min in the V-HeFT I trial (53). Therefore, protocols based on the assessment of submaximal exercise duration may not be ideal for multicenter trials because of difficulties in the choice of the baseline work rate. These protocols may actually require a repetition of the baseline test, up to when a workload just above the anaerobic threshold is found. Only in this way will the duration of the exercise at baseline be sufficiently short to allow detection of a change during follow-up. Submaximal exercise duration is also probably less reproducible and more sensitive to the effects of placebo, particularly when used in multicenter trials (53).
The 9-min treadmill test and the 6-min walk test are based on the measurement of the distance walked by the patient during a fixed period of time. They are well accepted by the patient and are easier to perform because they do not require specific equipment. Therefore, they will be increasingly used as submaximal protocols in studies of drug efficacy. However, as will be shown, they actually appear to measure maximal rather than submaximal functional capacity.
The 9-min treadmill test measures the distance walked during 9 min on a treadmill with a fixed 7° inclination. To better reproduce daily activity, the patient can stop to take a temporary rest during the examination (85). This exam has high reproducibility and allows easy differentiation among patients with different degrees of functional limitation(85,86). However, its clinical significance is very similar to that of the peak VO2 because the VO2 reached with this test averages 95 ± 5% of peak VO2(86), with a high correlation between these two measurements (86). Therefore, the 9-min treadmill test must be considered a test of maximal functional capacity.
The 6-min walk test measures the distance walked by the patient in a corridor during 6 min. The patient is encouraged to walk and, similarly to the previous examination, may stop to take a rest. The operator must periodically inform the patient about the time remaining to the end of the examination (87,88). This examination has shown a high degree of reproducibility, even if a first, preliminary exam should always be performed and excluded and a spontaneous improvement is always observed between the first and second of two consecutive examinations performed within a short period of time, e.g., 24 h (89). In drug efficacy studies, reproducibility may be increased by using the mean value of two consecutive tests performed within 1 day, both before and after therapy (89,90).
The 6-min walk distance has been shown to be related to prognosis in a substudy of the SOLVD trial (91). However, no study has yet assessed its independent prognostic value compared with peak VO2. This examination has also been used for assessment of the effects of therapy, i.e., β-blockade, in overcoming the limits of maximal exercise testing. Like the submaximal exercise duration, the 6-min walk test has also yielded significant results in a single-center study (92) but not in multicenter trials (93,94). It is interesting to note that, despite the lack of change in variables related to both maximal and submaximal exercise capacity, direct symptom assessment revealed a significant improvement with carvedilol compared to placebo (93,95). These data underscore both the difficulties in assessment of functional capacity with β-blocker therapy, because it blunts the cardiovascular response to exercise, and the limits of our available exercise protocols, which are less sensitive than simple direct symptom assessment in multicenter, placebo-controlled trials.
On the other hand, the 6-min walk test may have the significance of a maximal test when patients with moderate to severe CHF are studied. Measurements of VO2 during the 6-min walk test have shown that its clinical significance is different in normal subjects and in patients with CHF. The VO2 reached during the 6-min walk test averages 65 ± 16% of maximal VO2 in normal subjects, whereas it reaches 79 ± 24% in patients with CHF (96,97), with the majority reaching the anaerobic threshold and a significant percentage with VO2 values even higher than during the maximal test (97). Therefore, the 6-min walk test measures submaximal exercise performance in normal subjects and patients with only a mild limitation of functional capacity (98) but becomes an examination of maximal functional capacity in patients with severe CHF(96,97). Accordingly, the distance walked in the 6-min walk test has a high degree of correlation with peak VO2(99)(Fig. 4).
Physical activity can also be measured directly by the use of specific sensors of limb movements (54,100). These measurements are poorly related to quality of life scores and peak VO2(100). Day-to-day variability of the results is also high because of spontaneous fluctuations. It has been observed that measurements should be continued for at least 5-6 consecutive days to obtain reproducible results that can be used in drug efficacy studies (100). These measurements, even if certainly submaximal and related to everyday life, are therefore not practical and not reproducible enough to be applied in serial evaluations.
We have tried to examine some of the most widespread parameters used to measure functional capacity in patients with CHF. Unfortunately, functional capacity itself is not a homogeneous entity but has different features, with only a weak relation between them. The greatest difference is between maximal and submaximal functional capacity. The first expresses the maximal capacity of the cardiorespiratory system. It is therefore a measure of CHF severity with high prognostic value. However, it is poorly related to everyday physical activity when the patient performs mainly submaximal tasks. A change in maximal functional capacity may therefore imply an improvement in prognosis, whereas an improvement in submaximal indices may be more related to a change in symptoms. Unfortunately, no standard protocol to assess submaximal functional capacity is yet available.
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Proceedings of a symposium held in Apeldoorn, The Netherlands May 31, 1997