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European Journal of Heart Failure 2004 6(6):745-748; doi:10.1016/j.ejheart.2003.11.008
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© 2004 European Society of Cardiology

The effect of aspirin on the ventilatory response to exercise in chronic heart failure

Klaus K.A. Witte* and Andrew L. Clark

Department of Academic Cardiology, Castle Hill Hospital Castle Road, Cottingham Hull, HU16 5JQ, UK

* Corresponding author. Tel.: +44-1482-624073; fax: +44-1482-624071.. E-mail address: klauswitte{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Introduction: Patients with chronic heart failure (CHF) experience breathlessness and fatigue on exercise. One of the abnormalities seen on maximal exercise testing is an increased ventilatory response to exercise (VE/VCO2 slope). The cause of this is unknown, but is likely to be due to a combination of interacting peripheral and central factors. Recent data have demonstrated a relation between VE/VCO2 slope and prostaglandin levels in contracting muscles. The present study examined the influence of the presence of a potent non-selective prostaglandin inhibitor, aspirin, on the ventilatory response to exercise in a group of patients with CHF.

Methods: We investigated the ventilatory response to exercise of 120 consecutive patients in sinus rhythm attending a specialist heart failure clinic. We excluded those taking clopidogrel (six patients) and those on both warfarin and aspirin or taking other non-steroidal anti-inflammatory agents (five patients). The other 109 patients were grouped according to whether they were taking aspirin (n=52 (48%)) or not (n=57 (52%)). Each patient underwent echocardiography to assess left ventricular function, and exercise testing with metabolic gas exchange to derive peak oxygen consumption (pVO2) and the VE/VCO2 slope.

Results: The groups were similar in terms of age, (67 (13) vs. 66 (12) years; P=0.34) drug use, heart failure aetiology, left ventricular function (ejection fraction; 33.3 (9.4) vs. 31.8 (9.9)%; P=0.05)) and exercise tolerance (pVO2; 20.4 (5.3) vs. 19.9 (6.0); P=0.68, and VE/VCO2 slope; 35.4 (6.2) vs. 35.7 (9.3); P=0.73). There was no difference in the ventilatory response to exercise or the symptoms of breathlessness between the two groups.

Conclusions: Aspirin does not appear to affect exercise performance in CHF.

Key Words: Prostaglandins • Ventilation • Chronic heart failure

Received July 11, 2003; Revised October 1, 2003; Accepted November 19, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Chronic heart failure is a syndrome characterised by exercise intolerance due to breathlessness and fatigue [1]. Patients have reduced peak oxygen consumption (pVO2) [2] and an increased ventilatory response to exercise as demonstrated by an increase in the slope relating ventilation to carbon dioxide production (VE/VCO2 slope) [3–5]. The VE/VCO2 slope correlates inversely with pVO2, so that the greater the ventilatory response, the lower the exercise capacity [3,5]. Both pVO2 and VE/VCO2 are related to symptom scores and prognosis [6,7].

The cause of the increased ventilatory response to exercise in patients with CHF remains unclear. Skeletal muscle contains receptors, termed ergoreceptors that stimulate ventilation in response to work [8]. These receptors are overactive in heart failure and contribute significantly to the increased the ventilatory response to exercise [9]. This could be a consequence of increased sympathetic activity in CHF, and indeed acute sympathetic blockade can reduce submaximal ventilation during exercise in patients with CHF [10]. A further influence on ventilation during exercise might be through central chemoreceptors [11]. Arterial blood gas tensions are normal in chronic heart failure patients during exercise [12,13], but the reflexes associated with these chemoreceptors are overactive in CHF [14]. Other chemical mediators of the increased ventilatory response might include potassium [15,16] adenosine [17] or prostaglandins [18]. Under circulatory occlusion during handgrip exercise, prostaglandin levels correlated with the ventilatory response in a group of patients with CHF [18].

Aspirin and other prostaglandin inhibitors such as non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed frequently in patients with chronic heart failure, aspirin with the aim of ‘cardioprotection’ in patients with ischaemic heart disease, and NSAIDs for concomitant inflammatory or arthritic disorders. The aim of the present study was to establish whether the prostaglandin inhibition of aspirin at moderate doses has a clinically significant influence of on the ventilatory response to exercise in patients with chronic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
We examined the exercise tests of 120 consecutive patients in sinus rhythm attending a specialist clinic for heart failure. We excluded the results of six patients taking clopidogrel and five patients who were taking both aspirin and warfarin or other NSAIDs giving a study population of 109. 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 40% with no other cause of breathlessness apparent. To be included in the analysis, the condition had to be of at least 6 months duration, with no recent (<3 months) exacerbation or change in medication and on optimal therapy including beta-blockers and angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (AIIA). We did not include patients with neurological conditions, inducible ischaemia or a history of pulmonary disease. In order to eliminate the possible effects of atrial fibrillation we excluded patients with this rhythm disturbance. At the time of assessment, no patient was taking COX-2 inhibitors.

Each patient received a complete echocardiographic examination using a Vingmed Vivid 5 scanner (Horten, Norway) using M-mode to determine left ventricular end-diastolic diameter (LVEDD) and the modified Simpson's rule to calculate left ventricular volumes and ejection fraction (LVEF). 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. Patients 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 Pro, Würtzburg, Germany). A respiratory exchange ratio (RER), (VCO2/VO2) of >1.0 was taken to indicate maximal effort. The anaerobic threshold was calculated using the VO2/VCO2 slope method [19]. The regression slope relating ventilation to carbon dioxide production (VE/VCO2 slope) was calculated for the whole of exercise and from the start of exercise to the anaerobic threshold (sub AT VE/VCO2 slope) [20]. The subjects were asked to score their symptoms of breathlessness or fatigue between 0 and 10 (0 being no symptoms and 10 being maximal) on a standard scale of perceived exertion [21] at the end of each stage during the test. We related symptoms to ventilation by plotting the Borg score against ventilation and calculated the slope of this relationship for each test (Borg/VE slope) [20]. All patients underwent an initial familiarisation exercise test one week prior to the one used for the present analysis.

One physician, (KW) blinded to the patients’ therapy, analysed metabolic gas results and performed the statistical tests. For comparison of continuous data between the aspirin and non-aspirin sinus rhythm groups, we used Student's t-test and for categorical data we used the chi-squared test. Results are shown as means (S.D.) and we took a P-value <0.05 as significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Baseline patient characteristics are shown in Table 1. The patients were very similar in terms of age, height, weight, NYHA class and echocardiographic variables. Spironolactone and digoxin were prescribed more frequently in those not on aspirin, and doses of loop diuretics also tended towards being higher in this group, implying slightly more symptomatic heart failure. The average aspirin dose at the time of the exercise test was 132 (43) mg. The use of beta-blockers or their doses were not different between the groups.


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  		Table 1 Subject characteristics

 
The results of the peak exercise tests are shown in Table 2. Peak oxygen consumption, VE/VCO2 slope for the whole of exercise and the sub AT VE/VCO2 slope (data not shown) were not different between the two groups. Exercise time and peak RER were also the same. Symptoms of breathlessness (Borg/VE slope) were also not different between the groups.


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  		Table 2 Exercise variables according to use of aspirin

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study does not show a relation between exercise capacity or the ventilatory response to exercise and aspirin use in patients with CHF. Previous work has suggested that the increased ventilatory response seen in patients with chronic heart failure correlated with a local rise in prostaglandins in response to circulatory occlusion [18]. Prostaglandin inhibition might be a method to reduce the increased ventilatory response to exercise and the sensation of breathlessness in patients with CHF.

In the present study we could find no evidence that the use of aspirin conferred any benefit on the ventilatory response to exercise or exercise tolerance. The patients were not randomised in this retrospective analysis, but they were similar demographically, although those not taking aspirin seemed to have worse heart failure, requiring more spironolactone and digoxin, and having slightly higher loop diuretic requirements. Despite this, the VE/VCO2 slope was not lower in the aspirin group. Too few of our patients were taking high dose aspirin to allow us to make comparisons between different doses. It is therefore possible that higher doses of aspirin might have adversely affected the VE/VCO2 slope.

The ‘blanket’ prescribing of aspirin to CHF patients has been questioned [22], as there is little evidence of a reduction of thromboembolic risk with this strategy in patients with ischaemic heart disease or dilated cardiomyopathy [23,24]. Non-specific prostaglandin inhibitors such as aspirin and other traditional NSAIDs which inhibit both cycloxygenase enzymes (COX-1 and COX-2) can cause significant side effects in elderly patients, including gastrointestinal bleeding. They also reduce the mortality benefits of ACEi and beta-blockers in large randomised studies [25–28], and attenuate the improvements in pulmonary diffusion and exercise capacity of enalapril [29,30] and the beneficial vasodilating effects of loop diuretics [31]. The possible replacement of aspirin with clopidogrel or warfarin in these patients is currently under investigation in a multicentre study [32].

Our data show that patients taking aspirin do not have a lower ventilatory response to exercise in CHF than those not taking aspirin. Prostaglandin inhibition alone is unlikely to have a clinically significant influence on the ventilatory abnormalities seen in chronic heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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