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European Journal of Heart Failure 2004 6(5):551-554; doi:10.1016/j.ejheart.2003.08.004
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© 2004 European Society of Cardiology

Exercise-induced changes in exhaled nitric oxide in heart failure

Maurizio Bussotti, Daniele Andreini and Piergiuseppe Agostoni*

Centro Cardiologico Monzino IRCCS, Istituto di Cardiologia Università di Milano via Parea 4, 20138 Milan, Italy

* Corresponding author.E-mail address: Piergiuseppe.Agostoni{at}cardiologicomonzino.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: In heart failure abnormalities of pulmonary function are frequently observed as shown by hyperpnea, reduced lung compliance, reduced alveolar-capillary gas diffusion, positive methacholine challenge and, during exercise, early expiratory flow limitation. Nitric oxide (NO) might be related to all the above abnormalities.

Aims: We evaluated whether a correlation between exhaled NO (eNO) and lung function exists at rest and during exercise in heart failure.

Methods: We studied 33 chronic heart failure patients and 11 healthy subjects with: (a) standard pulmonary function, (b) lung diffusion for carbon monoxide (DLCO) including its subcomponents, capillary volume and membrane resistance and eNO both at rest and during light exercise, (c) maximal cycloergometer cardiopulmonary exercise test.

Results: Forced expiratory volume in 1 s (FEV1) was reduced in heart failure patients (83±17% of predicted), as was DLCO (75±18% of predicted) due to reduced membrane resistance (32.6±10.3 ml mmHg–1 min–1 vs. 39.9±6.9 in patients vs. controls, P<0.02). Exhaled NO was lower in patients vs. controls (9.7±5.4 ppm vs. 14.4±6.4, P<0.05) and was, during exercise, constant in patients and reduced in controls. No significant correlation was found between eNO and lung function. Vice-versa eNO changes during exercise were correlated with peak exercise oxygen consumption (r=0.560, P<0.001).

Conclusions: The hypothesis of a link between eNO and lung function in heart failure was not proved. The correlation between eNO changes during exercise and peak VO2 might be due to hemoglobin oxygenation, which binds NO to hemoglobin.

Key Words: Heart failure • Nitric oxide • Lung diffusion • Exercise

Received January 20, 2003; Revised June 20, 2003; Accepted August 28, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The lungs are significantly involved in chronic heart failure (CHF) with alterations in lung mechanics [1–3] and alveolar gas diffusion [4]. Indeed, in CHF, abnormalities in lung mechanics at rest are well known [2], as is exercise hyperpnea [5], which is due to the early occurrence of expiratory flow limitation [6]. Normal individuals improve lung mechanics during exercise as shown by the increase of the maximal flow/volume loop performed immediately after exercise [6–8]. This is probably due to an increase in airway caliber and lung compliance, which is absent in CHF patients [6] and in normal subjects after fluid loading [9]. CHF patients also show low gas diffusion across the alveolar-capillary membrane due to an increase in the alveolar capillary thickness and abnormal lung perfusion [10]. Furthermore, lung diffusion abnormalities correlate with exercise performance and prognosis in CHF patients [11].

However, nitric oxide (NO) may be involved in regulating lung mechanics, lung gas diffusion and lung blood flow. It is known that NO is a clinical hallmark of asthma and of its severity [12,13], that the pulmonary vasodilating action of NO increases lung diffusion, and that NO administration reduces pulmonary hypertension and improves lung perfusion. However, little is known about the correlation between NO changes during exercise and lung mechanics and diffusion both at rest and during exercise.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
We enrolled 33 consecutive CHF patients (aged 61.9±9.5 years, two female and 31 male) who were referred to our Heart Failure Unit. CHF was due to primary dilated cardiomyopathy in 20 cases and to ischemic cardiomyopathy in 13. Patients were required to be in a stable clinical condition for at least the previous 2 weeks, with echocardiographic left ventricle ejection fraction <40% and optimized, nitrate-free, heart failure therapy [14]. Eight patients were in NYHA class I, 16 were in class II and nine patients were class III. Treatment included diuretics (n=28), ACE-inhibitors (n=29), AT1 blockers (n=6), beta-blockers (n=26), spironolactone (n=15), and digoxin (n=3). Exclusion criteria were: clinical evidence of myocardial infarction in the last 6 months, COPD, peripheral vascular disease, pulmonary hypertension, effort-induced cardiac ischemia, angina, severe systemic hypertension or arrhythmia. We also evaluated 11 normal subjects as controls (age 61.8±6.4 years old, 11 male) chosen from hospital employees and patients’ relatives.

All subjects were evaluated by standard pulmonary function tests [15] which included lung diffusion capacity for carbon monoxide (DLCO) measured with a single breath – constant expiratory flow technique (Sensor Medics 2200, Yorba Linda, CA) [16]. We also measured lung diffusion subcomponents, capillary volume (VC) and membrane resistance (DM), applying the Roughton and Forster method [17]. For this purpose, subjects inspired a gas mixture with 0.3% CH4, 0.3% CO, 0.3% C2H2 balanced with nitrogen with 3 different oxygen fractions, equal to 20%, 40% and 60%, respectively. Expiratory NO was measured by chemiluminescence analyzer (NOATM 280, Sievers Instruments, Colorado, USA) using a standard on line technique following the ATS recommendations [18]. In brief: (a) exclusion of nasal NO was performed by closure of the velopharingeal aperture, by making subjects exhale against a respiratory resistance with a positive mouthpiece pressure (20 cm H2O); (b) expiratory flow was kept constant; (c) ambient NO contamination was prevented by use of a specific filter. We also asked the subjects to wash the oral cavity with HCO3Na 3% solution to reduce oral bacterial production of NO [19]. Exhaled NO was measured on line vs. time. It consisted of a washout phase followed by a plateau phase. We measured exhaled NO concentration (eNO) as the value of the plateau phase if exhalation was at least 6 s long with a plateau >3 s and if differences between three consecutive measurements were <10% [18]. Data reported are the mean of these three measurements.

DLCO, DM, VC, and eNO were measured on the cycloergometer in the sitting position at rest and during a 25-W constant workload exercise test. Measurements for DLCO and eNO were done on consecutive days between the third and fifth minute of exercise. On a separate day, a maximal cycloergometer exercise test, with a personalized ramp protocol and breath-by-breath analysis of ventilation and expiratory gases was performed.

The local ethics committee approved the study and patients provided written informed consent to participate in the study.

Data are reported as means±S.D. To normalize data, we used predicted equations of Quanjer et al. [20] and Jones [21] for standard pulmonary function and of Huang et al. [16] for DLCO. Differences between normal subjects and patients were analyzed by unpaired t-test. Correlations between variables were evaluated by linear regression analysis.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Mean left ventricle ejection fraction was 33±7% with left ventricle diastolic volume 201±60 ml. Pulmonary function tests revealed a reduction in FEV1 and FVC (Table 1) in HF patients compared with controls. Also, DLCO was lower in patients vs. control subjects (75±18% of predicted vs. 93±19, P<0.01) due to a difference in DM (table 2). During exercise DLCO increased both in patients and normal subjects due to a VC increase (table 2).


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  		Table 1 Pulmonary function test

 


Figure 1
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  		Table 2 Lung diffusion at rest and during constant workload exercise.

 
The cardiopulmonary exercise test revealed: peak exercise oxygen uptake (VO2) 17.3±3.8 ml min–1 kg–1 and 27.3±5.3* in patients and normal subjects, respectively; VO2 at anaerobic threshold 11.5±3.1 ml min–1 kg–1 and 17.1±5.1*; peak work rate 107±26 W and 166±40*; peak ventilation 52±13 l/min and 75±22* (*=P<0.001).

Resting eNO (table 3) was lower in patients compared to normal subjects. Changes during exercise were also different with a reduction in eNO in normal subjects but not in patients (table 3).


Figure 2
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  		Table 3 Exhaled nitric oxide concentration (eNo) at rest and during constant workload exercise.

 
Considering the entire study population there was almost no correlation between respiratory function tests and exercise induced changes in eNO (Table 4). However, peak VO2 was correlated to exercise induced changes in eNO (Fig. 1).


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  		Table 4 Linear regression beetwen rest-exercise eNO ({Delta}eNO) and pulmonary function in the entire population

 


Figure 3
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  		Fig. 1 Correlation between peak VO2 and eNO changes during constant workload exercise ({Delta}eNO=eNOrest–eNOexercise).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study confirms previous observations [14,22–24] that eNO at rest is lower in CHF patients compared to normal subjects and shows that during exercise eNO does not decrease in CHF patients as it does in normal subjects. eNO and its changes during exercise are not significantly related to any of the respiratory parameters evaluated with the exception of peak VO2. However, our observations were made during sub-maximal exercise; indeed the complexity of the measurements was mandatory to avoid strenuous exercise and, therefore, our findings should not be extended to peak exercise.

NO is produced in the upper respiratory tract, the trachea, the bronchi, the alveolar epithelium and the pulmonary circulation [19,24]. With the technique we used, nasal cavity and paranasal sinuses were excluded from sampling. It is unlikely that the difference in eNO observed between patients and controls is due to NO produced by pulmonary vasodilatation [24]. Indeed, VC at rest was similar between patients and controls, possibly because we did not study patients with severe heart failure who have a ‘compensatory’ increase in VC [25]. Furthermore, during exercise, the VC increasing due to pulmonary vessels recruitment is similar between patients and healthy subjects and there is no correlation between DLCO and VC changes during exercise and eNO measurements.

Standard pulmonary function and DLCO measured at rest are similar to that previously reported for patients with the same degree of CHF [3]. Indeed we and others observed a reduction of DLCO due to a low DM [26]. Resting eNO was lower in patients compared to normal subjects. This is a previously reported observation, the cause of which is still unclear, although several explanations have been proposed [14,22–24], including inhibition of constitutive NO synthesis associated with chronic pulmonary hypoxia [27]. It is unlikely that drug treatment influenced our results. Indeed, patients receiving nitrates were excluded from the analysis [14] and the beta-blocker we use, carvedilol, has not been shown to influence pulmonary function at rest and during exercise in heart failure patients [28].

We hypothesized a parallel between lung function and eNO at rest and during exercise in CHF. Indeed, an elevated eNO is an index of bronchoconstriction [12,13], and in CHF patients, there might be wheezes, particularly during heart failure exacerbation, and the methacholine challenge is usually positive [29]. Furthermore, NO has a pulmonary vasodilating action and lack of exercise-induced pulmonary vasodilatation is often reported in CHF patients. In contrast to what we expected, the correlations between lung function and eNO and its exercise-induced changes are absent or very weak (Table 4). As a consequence, eNO and its changes during exercise are not a cause or a marker of pulmonary function in CHF.

We observed a strong correlation between peak VO2 and {Delta}eNO. The reason for this, if a cause–effect relationship has to be suggested, is not a simple one. Stamler et al. [30] showed that hemoglobin undergoes to allosteric transition between the oxygenated and the de-oxygenated form, so that de-oxygenation releases NO and oxygenation binds NO to hemoglobin. It is possible that the changes in eNO we observed during exercise are due to a greater NO uptake in the lungs in healthy subjects vs. CHF patients related to a lower number of hemoglobin molecules flowing through the lungs. This might be due to a greater VO2 for the same workload in healthy subjects vs. HF patients or, if VO2 is the same, to a lower mixed venous hemoglobin saturation and hemoglobin blood concentration in CHF patients. Indeed, in CHF, anemia is frequently observed and exercise-induced hemoconcetration is limited [31,32].

In conclusion, we were not able to prove our hypothesis of a correlation between lung function and eNO in CHF patients and we believe that more studies are needed to evaluate the hypothesis of a link between hemoglobin oxygenation/de-oxygenation and eNO values.


   Acknowledgements
 
The authors acknowledge the superior technical assistance of Maria Luisa Scapin.


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

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