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European Journal of Heart Failure 2008 10(12):1224-1228; doi:10.1016/j.ejheart.2008.09.017
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© 2008 European Society of Cardiology

Dyspnoea versus fatigue: Additional prognostic information from symptoms in chronic heart failure?

Klaus K.A. Wittea,* and Andrew L. Clarkb

a Division of Cardiovascular and Diabetes Research LIGHT building, LS1 3EX, United Kingdom
b Department of Academic Cardiology, University of Hull Castle Hill Hospital, Hull, HU16 5JQ, United Kingdom

* Corresponding author. Division of Cardiovascular Medicine and Diabetes, LIGHT building, University of Leeds LS1 3EX, United Kingdom. Tel.: +44 113 3926000; fax: +44 113 2787206. E-mail address: klauswitte{at}hotmail.com (K.K.A. Witte).


   Abstract
Top
 Abstract
1. Introduction
 2. Aim
 3. Methods
 4. Results
 5. Discussion
 6. Conclusions
 7. Limitations
 References
 
Background: In non-heart failure populations, dyspnoea reported by the patient as the reason for stopping an exercise test is associated with a worse prognosis than fatigue. Patients with chronic heart failure (CHF) have exercise limitation due to breathlessness or fatigue, but it is unclear whether one symptom confers an adverse prognosis over the other.

Methods: Consecutive CHF patients underwent exercise testing with metabolic gas exchange. Upon stopping exercise the dominant symptom reported by the patients was recorded. Survival analyses were performed to establish predictors of mortality and relationships between symptoms and objective measures of exercise capacity.

Results: Data were analysed on 271 patients (219 men), mean age 67 (10) years, mean left ventricular ejection fraction 32 (8)%, and median follow-up 59 months (interquartile range 38). There were no differences in exercise variables, sex, NYHA class, body mass index and medical therapy between fatigued and dyspnoeic patients. At the censor date 92 (34%) patients had died. Deceased patients had a lower peak oxygen consumption (17.2 (4.6) versus 20.3 (5.6); p=0.0028). Although NYHA class was related to death at 36 months ({chi}2 value=7.3, p=0.026), reason for stopping was not ({chi}2 value=0.57, p=0.45).

Conclusion: Unlike in non-heart failure populations, dyspnoea as the reason for stopping an exercise test in CHF subjects is not associated with increased mortality. CHF patients should be assessed for treatments such as cardiac resynchronisation therapy by the degree of exercise intolerance, not the nature of their symptoms.

Key Words: Dyspnoea • Fatigue • Chronic heart failure

Received April 8, 2008; Revised August 25, 2008; Accepted September 25, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Aim
 3. Methods
 4. Results
 5. Discussion
 6. Conclusions
 7. Limitations
 References
 
Patients with chronic heart failure complain of exercise intolerance, usually due to breathlessness and fatigue [1]. This can be objectively assessed as a reduction in peak oxygen consumption (pVO2) during incremental exercise testing with metabolic gas exchange analysis [2]. Patients also have an increased ventilatory response to exercise as shown by an increase in the slope relating ventilation to carbon dioxide production (VE/VCO2 slope) [3,4]. The VE/VCO2 slope is abnormal throughout exercise [5], and correlates inversely with pVO2, so that the greater the ventilatory response, the lower the exercise capacity [3,4]. Impaired exercise capacity and a steeper VE/VCO2 slope are markers of a poor prognosis in patients with CHF [6,7]. Other information obtained during a symptom-limited exercise test in subjects with chronic heart failure includes a subjective statement by the patient of their reason for stopping, for example dyspnoea, fatigue or chest pain.

In large populations of healthy subjects and subjects with ischaemic heart disease performing cycle or treadmill-based exercise testing, exercise duration and peak workload are related to prognosis. However, in addition, subjects citing dyspnoea as a reason for terminating exercise have a worse prognosis than those stopping exercise due to fatigue or chest pain [8,9]. It is unknown whether the same prognostic information is available from symptom-limited testing of patients with chronic heart failure due to left ventricular dysfunction.


   2. Aim
Top
 Abstract
 1. Introduction
 2. Aim
3. Methods
 4. Results
 5. Discussion
 6. Conclusions
 7. Limitations
 References
 
To investigate whether patients with chronic heart failure stopping exercise due to dyspnoea have a different prognosis to those stopping due to fatigue.


   3. Methods
Top
 Abstract
 1. Introduction
 2. Aim
 3. Methods
4. Results
 5. Discussion
 6. Conclusions
 7. Limitations
 References
 
Consecutive patients under follow-up in a community-based heart failure clinic were invited to perform an exercise test with metabolic exchange as part of the assessment of their heart failure. Chronic heart failure was defined as the presence of symptoms of fatigue or breathlessness on exertion and a left ventricular ejection fraction on echocardiography of less than 45% with no other cause of breathlessness apparent. We excluded from the analysis, data from patients with neurological conditions, inducible myocardial ischaemia, a history of pulmonary disease, and patients with an FEV1 less than 80% of predicted. Patients limited by symptoms other than breathlessness and fatigue such as arthritic pain, were also excluded from the present analysis.

At the time of the assessment, each subject had a complete echocardiographic examination. They then underwent symptom-limited treadmill-based maximal exercise testing using a Bruce protocol modified by the addition of a ‘stage 0’ at onset consisting of 3 min of exercise at 1.61 km/h (1 mile/h) with a 5% gradient. Participants were encouraged to exercise to exhaustion. During the tests patients wore a tightly fitting facemask to which was connected a capnograph and a sample tube enabling on-line ventilation and metabolic gas exchange measurements (Jaeger Oxycon Delta, Würtzburg, Germany). A respiratory exchange ratio (RER), (VCO2/VO2) greater than 1 was taken to suggest a maximal effort. The anaerobic threshold was calculated using the VO2/VCO2 slope method [10]. The VE/VCO2 slope, which represents the relationship between ventilation (VE) (l min–1) and carbon dioxide production (VCO2) (l min–1), was calculated for each subject by simple regression of data collected throughout the whole of exercise [5]. At the end of each test the patients were asked to identify the most important symptoms causing them to stop exercising. The present data are limited to those patients identifying fatigue or dyspnoea as the major limiting symptom.

Results are reported as means (SD). We used unpaired Student's t-tests for between group comparisons of continuous variables, and chi-squared analysis to investigate the relationship between nominal variables such as survival, sex, NYHA class, and reason for stopping exercise. A Kaplan-Meier curve was constructed for survival of patients split by symptoms at end-exercise, and Cox proportional hazard ratios used to examine the influence of nominal and continuous data on survival. A p-value of <0.05 was taken to be significant. The study was approved by the local research ethics committee.


   4. Results
Top
 Abstract
 1. Introduction
 2. Aim
 3. Methods
 4. Results
5. Discussion
 6. Conclusions
 7. Limitations
 References
 
At the censor date (26th December 2007) 331 patients had undergone exercise testing. Of these, 290 patients had sufficient quality data achieved to be enrolled into the study and 19 stopped exercising due to chest pain or had their exercise test stopped by the observing physician due to important ST segment depression. These were excluded from the analysis. Of the remaining 271 patients, 56 (20%) did not achieve a peak RER >1.0. Although initial analyses were carried out without these individuals, including them had no effect on the overall results and the presented data include all 271 patients stopping exercise due to fatigue or dyspnoea.

The analysed population of whom 219 were men, had a mean age of 67 (10) years and 190 had ischaemic heart disease as the aetiology of their heart failure and 81 were non-ischaemic. There were 40 diabetics in the population. Most were in NYHA class II (n=195), although 60 patients were in NYHA class III. Mean left ventricular ejection fraction (LVEF) was 32 (8)% and mean left ventricular end-diastolic diameter (LVEDD) was 6.5 (1) cm. Median follow-up was 59 months (interquartile range 38), with no difference in follow-up time for the two patient groups (p=0.53). Table 1 shows data for patients grouped according to reasons for stopping exercise. There were no differences in exercise variables, sex, NYHA class, body mass index, heart failure aetiology, the presence of diabetes, and medical therapy between the two groups.


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  		Table 1 Variables according to reason for stopping

 
We had data up to 36 months for all subjects at the time of censoring. At this time, 92 (34%) patients had died. Deceased patients were older (72 (8) versus 66 (11) years; p=0.0019), with a lower baseline pVO2 (17.2 (4.6) versus 20.3 (5.6); p=0.0028) but there was no difference in LVEF (34 (10) versus 32 (7); p=0.30. Although NYHA class was also related to death at 36 months ({chi}2 value=7.3, p=0.026), reason for stopping was not ({chi}2 value=0.57, p=0.45).

Kaplan-Meier analysis showed that the survival curves for patients stopping due to dyspnoea and fatigue are superimposed (Fig. 1). The Cox-proportional hazard model for survival showed that survival was most closely related to peak oxygen consumption, beta-blocker use at the time of the test and age, but was not closely related to furosemide dose, reason for stopping, sex or VE/VCO2 slope (Table 2).


Figure 01
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  		Fig. 1 Kaplan-Meier cumulative survival plot for heart failure patients stopping exercise due to dyspnoea (D) or fatigue (F).

 


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  		Table 2 Cox proportion hazard ratios for death at 36 months

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Aim
 3. Methods
 4. Results
 5. Discussion
6. Conclusions
 7. Limitations
 References
 
Our data demonstrate for the first time that dyspnoea as the reason for stopping exercise during a symptom limited exercise test is not associated with an adverse outcome in patients with chronic heart failure. Hence, the symptoms experienced during an exercise test, in CHF patients with no important lung disease, offer no additional prognostic information over peak oxygen consumption and other baseline variables such as NYHA class and age. The present data confirm the importance of exercise capacity as measured by peak oxygen consumption in predicting outcome in patients with chronic heart failure. We also showed that patients taking a beta-blocker at the time of the exercise test had a lower long term mortality.

Previous work examining the prognostic information gained from the nature of symptoms during exercise in patients with coronary artery disease and control subjects undergoing peak exercise tests has suggested a greater mortality in those stopping exercise due to dyspnoea [8,9,11], although this has not been a consistent finding [12]. In the only study to recruit a ‘control’ population, Bodegard et al. showed that dyspnoeic patients had a higher frequency of ST segment depression, higher smoking incidence, and lower FEV1, perhaps alluding to a greater frequency of undiagnosed coronary artery disease or pulmonary disease, which might have contributed to the increased mortality in this group [8]. In addition, dyspnoea can be a symptom of coronary artery disease [13], hence one would expect patients with dyspnoea recruited from a ‘normal’ population to have a higher incidence of coronary deaths. The other two studies used patients referred for exercise assessment. Abidov et al. showed that in 18,000 subjects with and without known coronary artery disease undergoing myocardial perfusion imaging, dyspnoeic patients had a higher mortality. However, although the incidence of exercise-induced ischaemia was similar between those that stopped due to dyspnoea and those stopping for other reasons including chest pain, dyspnoeic subjects were older, with more dilated hearts, and had higher rates of atrial fibrillation, diabetes, and left ventricular hypertrophy. The authors did not report lung function, a common cause of impaired exercise in otherwise apparently healthy men [14], nor patient weight, although dyspnoeic patients were more likely to have conditions associated with obesity such as diabetes and hypertension. On the other hand, correction for left ventricular volume and perfusion defects on perfusion scanning, did not remove the association between dyspnoea and increased mortality. In 3000 patients referred for stress echocardiography testing, Bergeron et al. showed that patients referred for dyspnoea were more likely to have a subsequent myocardial infarction, but these patients were older, with a lower ejection fraction and higher incidence both of previous myocardial infarction and objective ischaemia than patients referred with chest pain [11]. Despite the shortcomings of these studies, it seems plausible that dyspnoea in otherwise asymptomatic truly ‘control’ subjects is associated with an adverse outcome, if only that they are more likely to have as yet undetected coronary artery disease, left ventricular dysfunction or pulmonary disease that is exposed by the exercise test. However, our data suggest that this is not the case in CHF.

5.1. Symptoms in chronic heart failure
The traditional haemodynamic model of the origins of symptoms in heart failure is coming under increasing scrutiny [15]. There is a poor relationship between exercise performance and left ventricular performance [16-21], despite increasingly sophisticated methods of assessing cardiac function [21], and therapies used to improve heart function such as positive inotropes [22,23], cardiac transplantation [24,25], or mitral valvuloplasty [26] have no immediate effect on exercise tolerance.

Our data have confirmed previous work that regardless of the limiting symptoms experienced during an exercise test, objective measures of exercise tolerance are similar in patient cohorts whichever symptom is dominant [1]. Previous data have shown that the type of exercise performed seems to influence whether individuals suffer breathlessness or fatigue. Slowly incrementing tests and cycle exercise are more likely to lead to fatigue [27], and cycle exercise is more often stopped by fatigue than breathlessness compared with treadmill exercise, even when the same level of exercise is performed [28,29]. These findings suggest that there is a common underlying pathology resulting in symptoms; and that the symptoms are variably reported by patients depending upon context [15].

5.2. The link between skeletal muscles and symptoms — the ergoreflex
Exercise capacity in heart failure patients is related to both muscle strength and bulk [30-32]. CHF is associated with a loss of muscle bulk from an early stage in the progression of the disease [33], and muscle strength [34] and endurance are reduced [35,36], independent of blood flow [35,37] and central factors [36].

How wasted, abnormal skeletal muscle might be responsible for the sensation of fatigue is fairly straightforward, but how it might lead to dyspnoea is less so. Skeletal muscle contains ergoreceptors, muscle receptors sensitive to work. Stimulation of these receptors during exercise leads to increased ventilation and sympathetic activation — the ergoreflex [38]. The degree of activation is in part related to the work performed per unit of muscle mass and to the metabolic state of the muscle [39]. The increased ventilatory response to exercise is proportional to the increased ergoreflex activity [40]. The concept of an exaggerated ergoreflex in patients with chronic heart failure, provides an elegant and unifying hypothesis explaining breathlessness, fatigue and the excessive sympathetic activation in these patients [2].


   6. Conclusions
Top
 Abstract
 1. Introduction
 2. Aim
 3. Methods
 4. Results
 5. Discussion
 6. Conclusions
7. Limitations
 References
 
Unlike control subjects and patients with coronary artery disease, our analysis did not identify a higher long term mortality in CHF patients stopping exercise during stress testing due to dyspnoea than those experiencing fatigue. Although it is feasible that in non-CHF datasets, dyspnoea might directly reflect cardiopulmonary limitation, in subjects with CHF, since exercise intolerance is the result of multiple factors, each of which may be dominant, the prognosis is dictated not by which one is dominant but the severity of the underlying condition. Lower peak oxygen consumption, greater age and the absence of a beta-blocker are the most important negative predictors of outcome in this population. Hence patients reporting fatigue should receive the same intensive therapy with beta-blockers, angiotensin-converting enzyme inhibitors and resynchronisation pacemakers as those reporting dyspnoea.


   7. Limitations
Top
 Abstract
 1. Introduction
 2. Aim
 3. Methods
 4. Results
 5. Discussion
 6. Conclusions
 7. Limitations
References
 
Our study is a retrospective analysis of data collected prospectively at a single heart failure unit, with a limited number of patients. However, our follow-up period is long and the event rate was high. Although our mean RER was 1.0, we included a modest number of patients who did not reach peak exercise capacity as determined by an RER>1.0. However, the lack of difference in exercise variables between those stopping with breathlessness and fatigue remained even without these individuals, hence we included them in order to maintain the generalizability of the data. Although we have information on lung function, we did not record smoking status which is a potential interacting factor.


   References
Top
 Abstract
 1. Introduction
 2. Aim
 3. Methods
 4. Results
 5. Discussion
 6. Conclusions
 7. Limitations
 References
 

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R. M Cubbon and K. K A Witte
Cardiac resynchronisation therapy for chronic heart failure and conduction delay
BMJ, April 28, 2009; 338(apr28_2): b1265 - b1265.
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