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(Circulation. 1995;92:47-53.)
© 1995 American Heart Association, Inc.

Articles

Dissociation Between Exertional Symptoms and Circulatory Function in Patients With Heart Failure

John R. Wilson, MD; Glenn Rayos, MD; T. K. Yeoh, MD; Patricia Gothard, RN; Karen Bak, RN

From the Cardiology Division of the Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to John R. Wilson, MD, Cardiology Division, Room CC-2218 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2170.

	Abstract

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Background Patients with heart failure frequently report exertional dyspnea and fatigue. These symptoms are usually attributed to circulatory dysfunction and therefore are typically treated with cardiovascular medications. Serial assessment of exertional symptoms has also become the principal method used to assess drug efficacy in heart failure. Nevertheless, the relation between exertional symptoms in heart failure and circulatory dysfunction remains uncertain.

Methods and Results This study was undertaken to investigate the relation between exertional symptoms, ventilatory and skeletal muscle dysfunction, and circulatory function in patients with heart failure. To this end, 52 ambulatory patients with heart failure underwent hemodynamic monitoring during maximal treadmill exercise testing. During exercise, the severity of dyspnea and fatigue was evaluated on a scale of 6 to 20 (Borg scale). The level of perceived exercise intolerance during daily activities was evaluated with the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. Maximal treadmill exercise increased the O₂ to 13.4±2.8 mL · min^-1 · kg^-1, the dyspnea score to 15.7±2.3, the fatigue score to 14.8±3.4, the pulmonary wedge pressure to 28±11 mm Hg, and the pulmonary artery lactate concentration to 34.5±16.3 mg/dL and decreased the pulmonary artery hemoglobin oxygen saturation to 30±9%. The level of perceived dyspnea had no relation to the pulmonary wedge pressure and correlated only minimally with the level of excessive ventilation (r=.39). The level of perceived fatigue correlated only weakly with blood lactate concentration (r=.55). Eleven patients (21%) exhibited a normal cardiac output and wedge pressure <20 mm Hg during exercise, 22 (42%) exhibited a normal cardiac output but wedge pressure >20 mm Hg during exercise, and 19 (37%) exhibited reduced cardiac output and wedge pressure >20 mm Hg during exercise. Despite these markedly different hemodynamic responses, all three groups exhibited similar levels of fatigue and dyspnea at comparable workloads and had comparable total scores for the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. There was no relation between the Living With Heart Failure Questionnaire and peak exercise O₂ and only a weak correlation between the Dyspnea-Fatigue Index and peak O₂ (r=.48).

Conclusions The level of exercise intolerance perceived by patients with heart failure has little or no relation to objective measures of circulatory, ventilatory, or metabolic dysfunction during exercise. In patients who report severe exertional symptoms, it may be desirable to directly measure hemodynamic response to exercise to ensure that these symptoms are due to circulatory dysfunction.

Key Words: heart failure • transplantation • exercise

	Introduction

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Exercise intolerance is one of the most common problems experienced by patients with heart failure.^{1 2 3} These patients frequently report exertional fatigue and dyspnea during normal daily activities. Patients with heart failure also frequently exhibit reductions in maximal exercise capacity during formal exercise testing.^{1 2 3}

At present, this exercise intolerance is usually attributed to circulatory dysfunction, since patients with heart failure often exhibit abnormal cardiac output and pulmonary wedge pressure responses to exercise.^{1 2 3} This assumption in turn has led most physicians to treat exertional dyspnea and fatigue primarily with cardiovascular medications in patients with heart failure. This assumption has also led to the widespread use of serial exercise testing and serial assessment of exertional symptoms to determine the efficacy of new treatments for heart failure.

Recently, however, there has been increasing evidence that exercise intolerance in heart failure is not solely due to circulatory factors. For example, several groups have shown that exercise training can improve exertional symptoms in patients with heart failure without changing hemodynamic function.^{4 5} We have shown that at least a quarter of patients with exertional fatigue exhibit normal leg blood flow responses to exercise, suggesting that inadequate flow is not responsible for their fatigue.⁶ There is also evidence that patients' perceived exertional symptoms may not reflect their actual exercise ability; Smith et al⁷ noted only a weak relation between peak exercise O₂ and New York Heart Association functional class in patients with heart failure.

The present study was undertaken to systematically investigate the relation between exertional symptoms and circulatory function in ambulatory patients with heart failure. To this end, we monitored hemodynamic responses to maximal treadmill exercise in patients and concurrently asked the patients to quantify their level of exertional fatigue and dyspnea according to the Borg scale, a standardized scoring system.⁸ We then examined the relation between the level of circulatory dysfunction and symptom scores. In addition, we examined the relation between hemodynamic function and patients' perceived functional intolerance during normal daily activities, as assessed with the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index.^{9 10 11}

	Methods

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Patient Population
Studies were performed on 52 ambulatory patients referred to the Heart Failure and Heart Transplantation Program at Vanderbilt University Medical Center. All patients had a history of chronic heart failure for >6 months, and all patients were ambulatory and were receiving digoxin, an angiotensin-converting enzyme inhibitor, and diuretics. Thirty-eight patients were men and 14 women. The average age was 49±10 years (range, 26 to 67 years). The left ventricular ejection fraction averaged 23±7%. Heart failure was attributed to coronary artery disease in 28 patients, to idiopathic cardiomyopathy in 22 patients, and to valvular heart disease in 2 patients.

Protocol
Patients underwent Swan-Ganz catheterization with exercise as part of their clinical evaluation. Before catheterization, all patients had performed at least one cardiopulmonary exercise test and therefore were familiar with treadmill exercise and respiratory gas analysis.

On the day of the catheterization, patients fasted for at least 3 hours before presenting to a special procedure room. All medications were continued except for diuretics; these were withheld the morning of the study. On arrival, the patients were given two questionnaires to evaluate their functional limitation: the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index.^{9 10 11}

The Minnesota Living With Heart Failure Questionnaire consists of 21 questions, each of which assesses the patient's perception of how his or her emotional and physical state is impaired by heart failure. The answer to each question ranges from a score of 0 (no impairment) to 5 (very much impaired), so that the total score can range from 0 to 105. The higher the score, the more severe the impairment. Questions 2 (rest during the day), 3 (walking and climbing stairs), 4 (working around the house), 5 (going away from home), 6 (sleeping), 7 (doing things with others), 12 (dyspnea), and 13 (fatigue) focus primarily on physical limitations and therefore were combined to obtain a physical limitation score. Questions 17 (feeling burdensome), 18 (feeling a loss of self-control), 19 (worry), 20 (difficulty concentrating and remembering), and 21 (feeling depressed) focus primarily on emotional limitations and therefore were combined to obtain an emotional limitation score.

The Dyspnea-Fatigue Index uses a scale of 0 to 4 to assess the magnitude of task that produces dyspnea and/or fatigue (0, symptomatic at rest; 4, symptomatic only with extraordinary activity), the pace of task that produces dyspnea and/or fatigue (0, symptomatic at rest; 4, all activities performed at normal pace), and the level of functional impairment (0, very severe; 4, none). Therefore, the composite index can range from 0 (severely limited) to 12 (no limitation).

After the patient completed the questionnaires, a 7F Swan-Ganz catheter was inserted via the right internal jugular vein. The patient was allowed to recover for 20 to 30 minutes, after which resting hemodynamic measurements were made, including pulmonary artery, pulmonary wedge, and right atrial pressures. Thermodilution cardiac outputs were measured in triplicate by injection of 10-mL boluses of iced saline and an Edwards thermodilution computer. Arterial blood pressure was measured by cuff sphygmomanometry. Pulmonary artery blood samples were obtained for lactate and hemoglobin O₂ saturation.

The patient then stood on a Marquette treadmill and was connected to a MedGraphics CardioO₂ System via a disposable pneumotach. The patient was also attached to a pulse oximeter via a device on the finger to noninvasively measure arterial oxygen saturation. Hemodynamic measurements and blood sampling were repeated. After 3 minutes of resting data acquisition, maximum symptom-limited exercise testing was performed according to a 3-minute Naughton protocol. At the end of each exercise stage and at peak exercise, hemodynamic measurements and blood sampling were repeated. Arterial hemoglobin O₂ saturation was monitored continuously via the pulse oximeter. In addition, the patient was asked to rate the level of dyspnea and leg fatigue by the Borg scale.⁸ This scale rates the level of perceived symptoms on a scale of 6 (none) to 20 (severe). After exercise, the Swan-Ganz catheter was removed and the patient was discharged home.

From the results of this study, each patient's hemodynamic response to exercise was classified as mild, moderate, or severe hemodynamic dysfunction. Patients with normal cardiac output responses to exercise and pulmonary wedge pressures that never exceeded 20 mm Hg during exercise were considered to have mild hemodynamic dysfunction. Patients with normal cardiac output responses to exercise but pulmonary wedge pressures that exceeded 20 mm Hg during exercise were considered to have moderate hemodynamic dysfunction. Patients with low cardiac output responses to exercise and pulmonary wedge pressures >20 mm Hg during exercise were considered to have severe hemodynamic dysfunction.

A reduced cardiac output response to exercise was defined as a cardiac output (L/min) <0.5xO₂+3 L/min. This lower limit was based on the studies of Higginbotham et al¹² but was consistent with the results of Damato et al¹³ and Becklake et al.¹⁴

To assess lactate responses to exercise, the anaerobic threshold was defined as the O₂ level at which lactate increased by 5 mg/dL over resting levels.

Derived Variables
Mean arterial blood pressure was calculated as the diastolic pressure plus one third of the pulse pressure. Arteriovenous O₂ difference was calculated as (hemoglobin concentrationx1.34 mL O₂/g hemoglobin)x(arterial–pulmonary artery hemoglobin oxygen saturation). Arterial oxygen saturation was measured noninvasively with the pulse oximeter. Fick cardiac output was calculated as the oxygen consumption divided by the arteriovenous O₂ difference. Thermodilution cardiac output was measured at rest, whereas only Fick cardiac output was measured in the upright position and during exercise.

The degree to which minute ventilation (VE) during exercise exceeded normal ventilatory levels was calculated as measured VEx100%/normal ventilation. The normal ventilatory level was calculated as 23.9xCO₂+12.6 L/min. This is the upper limit of normal (2 SEM above the average ventilation) calculated by Jones et al¹⁵ in normal subjects.

Measured Variables
Hemoglobin O₂ saturation was measured with a Ciba-Corning 2500 Co-Oximeter. Blood for lactate determination was deproteinized with cold perchloric acid and assayed with a spectrophotometric technique. Normal values at rest for this technique are 3 to 12 mg/dL.

Data Analysis
All data are expressed as mean±SD. Differences between groups were evaluated by ANOVA. Correlations between variables were assessed by least-squares regression analysis. A value of P<.05 was considered statistically significant.

	Results

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Hemodynamic responses to exercise for the entire group are summarized in Table 1. The overall response was characterized by a reduced peak exercise O₂ of 13.4±2.8 mL · min^-1 · kg^-1 and increases in pulmonary wedge pressure and lactate concentration. However, individual patient hemodynamic responses varied widely. Eleven patients (21%) exhibited mild hemodynamic dysfunction, or normal cardiac output responses and wedge pressures <20 mm Hg at peak exercise. Twenty-two patients (42%) exhibited moderate hemodynamic dysfunction, or normal cardiac output responses but wedge pressures >20 mm Hg during exercise. Only 19 patients (37%) exhibited severe hemodynamic dysfunction, or both a reduced cardiac output and an increase in wedge pressure >20 mm Hg during exercise. Hemodynamic responses of these three groups are shown in Table 2 and Fig 1.

View this table: [in this window] [in a new window]   Table 1. Hemodynamic and Symptom Responses to Exercise

View this table: [in this window] [in a new window]   Table 2. Hemodynamic Measurements at Peak Exercise in Patients With Mild, Moderate, and Severe Hemodynamic Dysfunction

View larger version (26K): [in this window] [in a new window]   Figure 1. Graphs showing hemodynamic response to exercise in patients with mild, moderate, and severe hemodynamic dysfunction. See "Methods" for definitions of hemodynamic groups.

Despite these widely differing hemodynamic responses to exercise, peak exercise O₂ was not significantly different in the three groups (Table 3). Peak exercise O₂ averaged 14.0±3.8 mL · min^-1 · kg^-1 (range, 8.6 to 19.6) in the mild dysfunction group, 14.1±2.5 mL · min^-1 · kg^-1 (range, 8.6 to 17.8) in the moderate dysfunction group, and 12.3±2.1 mL · min^-1 · kg^-1 (range, 8.5 to 15.3) in the severe dysfunction group (P=NS).

View this table: [in this window] [in a new window]   Table 3. Characteristics of Patients With Mild, Moderate, and Severe Hemodynamic Dysfunction

Symptom responses to treadmill exercise for all 52 patients are illustrated in Fig 2. On average, patients reported very similar levels of dyspnea and fatigue during treadmill exercise. Symptom responses in the three hemodynamic subgroups are illustrated in Fig 3. Despite markedly different hemodynamic responses to treadmill exercise, all three groups reported similar levels of fatigue and dyspnea during treadmill exercise.

View larger version (16K): [in this window] [in a new window]   Figure 2. Borg Dyspnea chart 3, showing perceived dyspnea and fatigue during maximal treadmill exercise testing.

View larger version (19K): [in this window] [in a new window]   Figure 3. Graphs showing dyspnea and fatigue levels during treadmill exercise in patients with mild, moderate, and severe hemodynamic dysfunction. See "Methods" for definitions of hemodynamic groups.

To determine whether the symptom of dyspnea was related to objective measures of pulmonary dysfunction, the dyspnea score was correlated with the pulmonary wedge pressure during exercise and with the degree to which minute ventilation exceeded normal levels. There was no relation between perceived dyspnea and the pulmonary wedge pressure during exercise (Fig 4). There was a very weak correlation between the level of dyspnea and the degree to which minute ventilation exceeded the normal level (r=.39, P<.02) (Fig 4). However, patients with comparable levels of perceived dyspnea exhibited ventilatory levels ranging from totally normal to markedly abnormal.

View larger version (21K): [in this window] [in a new window]   Figure 4. Plots showing relation between perceived exertional symptoms and objective measures of exercise dysfunction. VE indicates minute ventilation.

To determine whether the sensation of fatigue correlated with a measure of skeletal muscle activation, we correlated the fatigue score with lactate concentration. There was a modest correlation between these two variables (r=.55, P<.01) (Fig 4). However, the relation between the level of fatigue and the lactate concentration varied widely from patient to patient. Some patients reported severe fatigue even though their blood lactate levels were unchanged from resting levels. Other patients exhibited markedly elevated lactate levels but denied any perception of fatigue. The fatigue score also correlated modestly with pulmonary artery hemoglobin oxygen saturation (r=.50, P<.01), but also with wide variability among patients.

Questionnaires
The total score on the Minnesota Living With Heart Failure Questionnaire averaged 55±19 and ranged from 14 to 88. The Dyspnea-Fatigue Index averaged 5.1±2.2 and ranged from 0 to 9.

There was no correlation between peak exercise O₂ and the total score of the Living With Heart Failure Questionnaire (Fig 5). Peak exercise O₂ also did not correlate with the physical or emotional limitation score. There was a significant but very weak correlation between peak exercise O₂ and the Dyspnea-Fatigue Index (Fig 5).

View larger version (27K): [in this window] [in a new window]   Figure 5. Plots showing relation between questionnaire results and peak exercise oxygen consumption (VO2) and the anaerobic threshold during maximal treadmill exercise testing.

Questionnaire scores were also correlated with the anaerobic threshold, the O₂ level at which lactate increased by 5 mg/dL over resting levels. Both the Dyspnea-Fatigue Index and the composite score of the Living With Heart Failure Questionnaire correlated with the anaerobic threshold (Fig 5). However, the degree of correlation was extremely weak.

There was no correlation between any questionnaire score and either the peak exercise cardiac index or peak exercise pulmonary wedge pressure. In addition, despite markedly different hemodynamic responses to exercise, the three hemodynamic groups exhibited similar composite scores for the Minnesota Living With Heart Failure Questionnaire (mild, 50±26; moderate, 60±13; severe, 52±21) and the Yale Dyspnea-Fatigue Index (mild, 4.3±2.7; moderate, 5.3±1.9; severe, 5.5±2.3) (all P=NS).

	Discussion

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On the basis of previous reports that patients with heart failure exhibit hemodynamic dysfunction during exercise,^{1 2 3} it is now widely assumed that a close link exists between the exertional symptoms reported by patients with heart failure and the severity of hemodynamic dysfunction. As a result, most physicians treat these exertional symptoms with pharmacological interventions designed to improve hemodynamic function. The severity of exertional symptoms is frequently used to time referrals to heart transplant programs, with symptomatic patients being referred for transplant evaluation, while asymptomatic patients are often treated with medical therapy. Pharmaceutical companies and the Food and Drug Administration rely heavily on exercise testing and symptom questionnaires to evaluate the efficacy of new drugs in heart failure.

The link between exertional symptoms and hemodynamic function, however, has never been systematically examined in patients with heart failure. Previous studies have demonstrated that peak exercise O₂ correlates weakly, if at all, with ejection fraction in such patients, leading to the general recognition that systolic cardiac function is not a key determinant of exercise capacity.^{3 7 16} Prior studies have also demonstrated that peak exercise O₂ does not correlate closely with New York Heart Association functional class or results of quality-of-life questionnaires,^{3 7} suggesting that a patient's maximal exercise capacity does not necessarily indicate symptom status during normal daily activities. However, it remains unclear whether the symptoms experienced by a patient at a given work level are related to the degree of cardiac output reduction or the level of intrapulmonary pressure elevation. It is also unclear whether the level of fatigue or dyspnea reported by patients correlates with objective indexes of muscle and lung dysfunction.

The present study was undertaken to investigate both these issues. First, we examined the relation between symptoms and the level of hemodynamic dysfunction. Exertional symptoms were measured by patients' rating of the level of dyspnea and fatigue during treadmill exercise according to a standardized scoring system called the Borg scale.⁸ Each patient also completed two questionnaires—the Living With Heart Failure Questionnaire and the Dyspnea-Fatigue Index—to assess exercise intolerance during normal daily activities.^{9 10 11}

Our second objective was to examine the relation between symptoms and objective measures of lung and skeletal muscle dysfunction. Specifically, we sought to determine whether patients who report exertional dyspnea exhibit objective evidence of pulmonary dysfunction such as elevated pulmonary wedge pressure and excessive ventilatory levels. To determine whether the presence of fatigue is accompanied by objective signs of skeletal muscle dysfunction, the level of leg fatigue was correlated with blood lactate concentration.

Hemodynamic Responses to Exercise and Exertional Symptoms
As a group, patients in this study exhibited hemodynamic and metabolic responses to exercise comparable to those of previous studies, including reduced peak exercise O₂, elevated pulmonary wedge pressure, and increased lactate levels.^{1 2 3} However, individual responses to exercise varied widely. Eleven of the patients, or 21% of the group, exhibited cardiac output responses to exercise within the normal range and had pulmonary wedge pressures that remained below 20 mm Hg, consistent with mild hemodynamic dysfunction. Forty-two percent of the patients had normal cardiac output responses to exercise but pulmonary wedge pressures >20 mm Hg, consistent with moderate hemodynamic dysfunction. Only 19 of the patients, or 37%, exhibited both reduced cardiac outputs and wedge pressures >20 mm Hg, a response assumed to be characteristic of patients with heart failure.

Despite these markedly different hemodynamic responses, all three groups exhibited similar symptom profiles. As illustrated in Fig 3, the level of dyspnea and fatigue were nearly identical in the three groups during treadmill exercise. Patients in the three groups also reported similar levels of exertional symptoms on the Living With Heart Failure Questionnaire and the Dyspnea/Fatigue Questionnaire.

These observations strongly suggest that the level of exertional symptoms reported by patients with heart failure does not reflect the level of hemodynamic dysfunction. This finding is not particularly surprising. Exercise physiologists have long been aware that exertional symptoms are influenced by multiple factors in addition to cardiac function, such as musculoskeletal status, body composition, motivation, and tolerance of discomfort. For example, individuals who are obese are likely to experience more symptoms than patients who are not obese. Symptoms during daily activities can be controlled by avoiding certain activities and by reducing the pace of the activities.

One noncardiac factor that may be particularly important in patients with heart failure is skeletal muscle deconditioning. A number of recent studies have shown that patients with heart failure develop skeletal muscle changes consistent with muscle deconditioning and exhibit improved exercise capacity with exercise training.^{4 5} It seems likely that muscle deconditioning contributed to the exercise intolerance of many of the patients in this study, particularly the patients with mild and moderate hemodynamic dysfunction who exhibited early increases in lactate levels despite normal cardiac output responses to exercise.

Relation Between Symptoms, Ventilation, and Metabolism
Our data further suggest that the exertional symptoms reported by patients also do not reflect the severity of skeletal muscle or lung dysfunction. During treadmill exercise, the levels of dyspnea had no relation to the pulmonary wedge pressure. Patients with totally normal pulmonary wedge pressures reported as much dyspnea as patients with markedly elevated wedge pressures. The level of excessive ventilation had only a very weak relation to the presence of dyspnea.

The presence of fatigue was only weakly related to the level of blood lactate. The accumulation of lactate in skeletal muscle is probably not responsible for the development of muscle fatigue^{17 18} but empirically provides an objective marker of skeletal muscle fatigue. A number of patients reported severe leg fatigue with virtually no increase in blood lactate levels, whereas other patients denied any fatigue despite markedly elevated levels.

Further evidence that the symptoms of dyspnea and fatigue do not reflect specific abnormalities of the lungs and skeletal muscle comes from the close relation between these two symptoms during exercise. As noted in Fig 2, most patients reported nearly identical levels of dyspnea and fatigue at each workload, suggesting that these two symptoms are interrelated and may reflect primarily the perceived intensity of exercise rather than specific abnormalities of a particular organ system. Interestingly, normal subjects also report similar levels of dyspnea and fatigue during exercise.¹⁹

The lack of a relation between particular symptoms and objective evidence of lung and skeletal muscle dysfunction has previously been noted by Sullivan et al.²⁰ These investigators measured hemodynamic, ventilatory, and lactate responses to bicycle exercise in a group of patients and, at peak exercise, asked them to indicate whether they were limited primarily by fatigue or dyspnea. Our experience is that this is a somewhat misleading question, since patients report similar levels of both symptoms and will only reluctantly pick one symptom as more severe. Nevertheless, Sullivan et al noted that the limiting symptom had no relation to the level of lung or skeletal muscle dysfunction. For example, patients who were limited primarily by dyspnea had ventilatory levels similar to those of patients limited by fatigue.

In a study specifically designed to examine the link between dyspnea and lung function, Mancini et al²¹ also observed no relation between ventilatory levels and dyspnea. However, they did note that the level of dyspnea reported by patients at a given workload correlated modestly with maximal inspiratory pressure, maximal expiratory pressure, FEV₁, and the tension-time index, a measure of lung work. They interpreted these findings as evidence that the sensation of dyspnea is related to respiratory muscle function. However, as in the present study, they noted that patients reported nearly identical symptoms of fatigue and dyspnea during exercise, making it likely that these symptoms are interrelated and that dyspnea is not a specific indicator of lung dysfunction.

Clinical Implications
Results of this study have several major clinical implications. First, our findings suggest that physicians should no longer assume that exertional symptoms in patients with heart failure indicate pump dysfunction and therefore should no longer rely solely on pharmaceutical interventions to treat these symptoms. The possibility that exertional symptoms are related to muscle deconditioning, obesity, and other noncardiac factors should be considered. If necessary, direct hemodynamic monitoring during exercise should be used to interpret exertional symptoms.

Conversely, the absence of exertional symptoms should not be considered definite evidence that cardiac pump function is preserved. In this study, several patients with severe hemodynamic dysfunction during exercise and severe exercise impairment denied significant exertional symptoms. Such patients should probably be considered for heart transplantation on the basis of a poor long-term prognosis.^{16 22 23} Such patients are probably best detected by maximal exercise testing.

Our findings further suggest that pharmaceutical companies and the Food and Drug Administration should reconsider the way new drugs are evaluated in heart failure. The typical method used to assess new drugs is to conduct a randomized, double-blind study in a broad range of patients. These patients are usually selected by their demonstrating reduced exercise capacity with some type of exercise test, either maximal or submaximal. No attempt is made to clarify the reason for exercise intolerance or the presence of pump dysfunction. Our findings suggest that this approach results in the enrollment of many patients with little or no hemodynamic dysfunction. Inclusion of such patients will make it more difficult to prove the efficacy of a drug. A more appropriate method of detecting drug efficacy might be to evaluate hemodynamic responses to exercise in all patients being considered for study and then to include only patients with significant hemodynamic dysfunction.

Ideally, such an approach would reduce the number of patients required in studies and improve the detection of effective agents. It should be emphasized, however, that this approach is not necessarily superior. Prior studies suggest that acute hemodynamic responses to pharmacological agents do not predict long-term changes in exercise capacity.²⁴ On the basis of this finding, use of invasive hemodynamic measurements to guide therapeutic interventions has been largely abandoned. This decision to ignore hemodynamic parameters may have been premature, however. The value of using hemodynamic measurements to select patients for therapeutic trials has never been directly evaluated. Moreover, the conclusion that changes in hemodynamic parameters do not predict long-term response is based primarily on retrospective analyses of data drawn from multiple interventional trials.²⁴ The value of using hemodynamic measurements to guide therapeutic interventions still needs to be prospectively tested.

	Acknowledgments

 
This study was supported by a grant from the Delaware Chapter of the American Heart Association.

Received January 18, 1995; revision received March 1, 1995; accepted March 5, 1995.

	References

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