Skip Navigation

European Journal of Heart Failure 2003 5(5):639-643; doi:10.1016/S1388-9842(03)00107-7
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Adachi, H.
Right arrow Articles by Ito, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Adachi, H.
Right arrow Articles by Ito, H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2003 European Society of Cardiology

Nitric oxide exhalation correlates with ventilatory response to exercise in patients with heart disease{star}

Hitoshi Adachia,*, Shigeru Oshimaa, Shigeki Sakuraia, Takuji Toyamaa, Hiroshi Hoshizakia, Koichi Taniguchia and Haruki Itob

a Gunma Prefectural Cardiovascular Center 3-12, Kameizumi, Maebashi, Gunma 371-0004, Japan
b The Cardiovascular Institute Tokyo, Japan

* Corresponding author. Tel.: +81-27-269-7455; fax: +81-27-269-1492. E-mail address: h-adachi{at}ops.dti.ne.jp


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Aims: It is controversial whether or not pulmonary nitric oxide (NO) production, reflected in the end-tidal alveolar NO concentration, is diminished in patients with heart failure. Since pulmonary perfusion is regulated by NO production, decreased NO production in the pulmonary vasculature is assumed to result in diminished lung perfusion and further increases in ventilation–perfusion mismatch. The aim of this study is to investigate whether exhaled NO correlates with both exercise-induced hyperpnea and exercise tolerance in patients with heart disease.

Methods and Results: Forty-two patients with heart disease were enrolled (history of prior myocardial infarction (n=19), dilated cardiomyopathy (n=2), hypertensive heart disease (n=5) and prior open-heart surgery (n=16)). During cardiopulmonary exercise testing, exhaled air was collected and end-tidal NO (ETNO) was measured using a chemiluminescent method. Peak ETNO was found to correlate positively with both ventilatory anaerobic threshold (r=0.468) and peak VO2 (r=0.562). The VE-CO2 slope, which reflects the ventilatory response to exercise, correlated negatively with peak ETNO (r=–0.588).

Conclusion: These data indicate that NO exhalation correlates, inversely, with the ventilatory response to exercise and directly with exercise intolerance, although the weakness of the correlation coefficient suggests there may be other possible mechanisms.

Key Words: Nitric oxide • Exercise hyperpnea • VE-VCO2 slope • Chronic heart failure

Received November 20, 2002; Revised January 30, 2003; Accepted June 16, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Exercise tolerance is often reduced in patients with heart disease. This is partially due to excessive ventilation during exercise [1,2]. Exercise hyperpnea occurs when the physiological dead space and ventilation–perfusion mismatch increases [3–5]. In these patients, attenuated exercise-induced pulmonary vessel dilation results in an increase in physiological dead space.

Nitric oxide plays an important role in vasodilation [6,7]. Diminished NO production in pulmonary vessels induces increased ventilation–perfusion mismatch. It has previously been reported by ourselves and by other investigators that NO production is attenuated in heart failure patients [8–10]. However, other studies suggest that NO production in these patients is augmented in order to compensate for limited vessel dilation [11,12]. Controversy still exists about whether or not NO production is increased in patients with heart disease.

Recently, other investigators have reported techniques for the measurement of exhaled NO [13,14]. NO is labile and quickly metabolized in blood [15]. Therefore, it is not only difficult to accurately measure NO production, but also impossible to determine the origin of the NO from blood samples. However, NO is more stable in air. NO in exhaled breaths can be used to detect the quantity of NO production from the lung fields. Measurement is optimized when end-tidal gas is used, since endothelial gas is released into the alveolar space.

We investigated the correlation between the ventilatory response to exercise and NO production from the lungs, by analyzing the exhaled air in patients with heart disease.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
Forty-two patients with heart disease were enrolled. Basal diseases were as follows: history of prior myocardial infarction (n=19), dilated cardiomyopathy (n=2), hypertensive heart disease (n=5) and prior open-heart surgery (n=16). New York Heart Association functional class was: class I (n=8), class II (n=24) and class III (n=10). No patients with pulmonary disease were included. The mean age of the patients was 60±10 years. Gender breakdown was as follows: male 37, female five. Angiotensin converting enzyme inhibitors were prescribed to most of the patients. In 34 patients, nitrates were prescribed. Those who were taking beta-blocking agents were excluded from this study. Ethical approval for the study was granted by the Gunma Prefectural Cardiovascular Center Subjects Committee. All subjects gave informed consent.

Cardiopulmonary exercise testing was performed using the ramp protocol. Equipment used included a cycle ergometer (MedGrafics, St. Paul, MN), breath-by-breath gas analyzer (MINATO 280S, Minato Ikagaku, Osaka, Japan) and electrocardiograph recorder (Fukuda Denshi, Tokyo, Japan). A small-sized facemask, which just covered the mouth, was used to collect exhaled gas samples. During our experiments, we obstructed the nasal airway with a nose-clip and also used a mouthpiece to reduce contamination by NO from the nose.

A chemiluminescent analyzer (Sievers, Toronto, Canada) was used to measure NO during exhalation. Eight consecutive exhaled breaths at the peak exercise level were averaged and expressed as the peak end-tidal NO (ETNO).

Twelve patients also gave informed consent for the measurement of cardiac output at peak exercise. Cardiac output was measured by the dye-dilution method using 5 mg of indocyanin green [16,17].

Anaerobic threshold was determined using the V-slope method [18]. The slope of the ventilatory equivalent of carbon dioxide (VE-VCO2 slope) was assessed by linear regression analysis of the breath-by-breath plot as previously reported [19].

We divided subjects into two groups according to the value of the VE-VCO2 slope: subjects whose VE-VCO2 slope was below the average value (Group A) and those whose VE-VCO2 slope was above average (Group B).

Left ventricular ejection fraction was measured by echocardiography using Simpson's method.

Data are expressed as mean±S.D. The difference between the two groups was assessed by the unpaired t test. Linear regression analysis was performed to evaluate the relationship between ETNO and other parameters obtained from cardiopulmonary exercise testing. Values of P<0.05 were considered significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
All patients performed the cardiopulmonary exercise test until exhaustion without complication. The mean respiratory exchange ratio was 1.14±0.04 at peak exercise. The mean value of the ventilatory anaerobic threshold was 12.4±2.7 ml–1 min–1 kg–1 and the peak VO2 was 18.0±5.1 ml–1 min–1 kg–1. The average VE-VCO2 slope was 33.3±9.4.

The correlation between VE-VCO2 slope and ETNO is shown in Fig. 1. As the NO concentration in the alveolus diminishes, the VE-VCO2 slope increases, i.e. the ventilatory response to exercise is augmented (r=–0.588). When divided into two groups, peak ETNO was higher (P<0.01) in Group A (92.8±10.6 ppb) than in Group B (79.9±10.9 ppb).


Figure 1
View larger version (7K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Correlation between ventilatory equivalent of carbon dioxide (VE-VCO2 slope) and end-tidal nitric oxide concentration.

 
Correlation between ETNO and exercise tolerance is shown in Fig. 2. Both ventilatory anaerobic threshold and peak VO2 correlated positively (r=0.468 and 0.562, respectively) with ETNO.


Figure 2
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Correlation between exercise capacity and end-tidal nitric oxide (ETNO) concentration. Left panel: Anaerobic threshold vs. ETNO. Right panel: Peak VO2 vs. ETNO.

 
Peak VO2/HR correlated positively (r=0.452) with peak ETNO (Fig. 3). Since peak VO2/HR is a product of stroke volume and arterial–venous O2 difference and arterial–venous O2 difference is uniform regardless of the basal disease, peak VO2/HR is assumed to represent cardiac function during exercise. Therefore, ETNO during exercise should correlate with cardiac function during exercise.


Figure 3
View larger version (7K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Correlation between peak VO2/HR and end-tidal nitric oxide concentration. Peak VO2/HR is a representative of stroke volume. When stroke volume at peak exercise levels is low, nitric oxide production at the peak of exercise is also low.

 
Results of cardiac output measurement at peak exercise are shown in Fig. 4. Correlation coefficient between cardiac output and peak ETNO is 0.468.


Figure 4
View larger version (6K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Correlation between end-tidal nitric oxide production and cardiac output.

 
There was no significant difference in left ventricular ejection fraction (Group A: 65.4±12.0%, Group B: 56.4±14.0%) or diastolic function (E/A ratio; Group A: 1.07±0.13, Group B: 1.04±0.13). That is, cardiac function at rest was not different within the two groups.

Respiratory rate, tidal volume and minute ventilation at 20 W exercise are shown in Fig. 5. Although there were no significant differences, patients in Group B tended to have lower tidal volume and higher respiratory rate than in Group A. Minute ventilation in Group B was significantly higher than that in Group A.


Figure 5
View larger version (11K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Bar graph of respiratory rate (RR), tidal volume (TV) and minute ventilation (VE) at 20 W exercise in Group A and Group B.

 
The ratio of increase in ETNO to VE from 0 to 20 W for Group A was 0.86±0.16 and for Group B was 0.73±0.15. This difference was significant.

Since nitrates are known to be NO donors, we investigated the effect of nitrates on ETNO at peak exercise. The peak ETNO of patients with nitrates was 87.5±12.6 ppb, compared to 90.0±10.8 ppb in patients without nitrates, this difference was not significant.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
We have shown a correlation between NO concentration in the end-tidal alveolar gas and both ventilatory response to exercise and exercise tolerance, in patients with heart disease. When NO concentration from the lung fields was decreased, ventilatory response to exercise was increased and exercise tolerance was reduced.

There is some disagreement about the origin of NO in exhaled air [20–23]. Nasal mucous membranes yield a large amount of NO [24]. Therefore, NO in exhaled air includes NO from nasal mucous membranes, as well as tracheal membranes and alveoli. Due to our measuring method using a nose-clip, the NO concentrations in our study are similar to those reported in prior investigations, which have measured NO concentrations in the lower airway using the intubation technique [25]. Hence, we believe that no contamination of the samples by nasal NO occurred in our study.

Since the last-part of an exhaled tidal volume is gas from the lung alveoli, the end-tidal gas NO concentration is assumed to be a reflection of intra-alveolar NO. Alveoli are surrounded by pulmonary capillary cells and alveolar epithelial cells and NO is produced in response to shear stress [26]. Since alveoli are located at the end of the airways, local airflow velocity and shear stress do not vary greatly. However, blood flow in the capillary bed changes dramatically during exercise, and as a result there is an increase in shear stress upon endothelial cells. Therefore, the change in NO concentration in the alveoli is assumed to be produced by the capillary endothelial cells.

Heart failure patients with a high VE-VCO2 slope are known to have a rapid and shallow breathing pattern. As shown in Fig. 5, patients in Group B tended to have higher respiratory rate and lower tidal volume and they had a significantly higher minute ventilation at a given work rate than those in Group A. Since augmented minute ventilation dilutes gas concentration, it is possible that the lower ETNO in Group B is not due to the diminished NO production, but due to simply the dilution effect accompanying the increase in VE. However, the ratio of ETNO increment compared with VE was lower in patients with high VE-VCO2 slope (Group B) than those with low VE-VCO2 slope (Group A). This result suggests that the lower ETNO in Group B is caused by a deteriorated NO production and not by dilution.

NO is labile and disappears within a few seconds when in contact with hemoglobin [15]. As a result, NO production from the pulmonary vasculature cannot be detected using peripheral venous blood samples. In air, however, the half-life of NO is longer (more than 4–8 s). Furthermore, since gas in the alveoli is exhaled within a few seconds, the ETNO reflects NO production by the pulmonary vascular bed.

Increases in the VE-VCO2 slope during exercise are partly due to an increase in ventilation–perfusion mismatch [1,2]. Decreased pulmonary perfusion results in an increase in physiologic dead space. This results in an increase in ventilation–perfusion mismatch. Since NO is a potent vasodilator, attenuation of NO production in the pulmonary vessels during exercise may play an important role in diminished pulmonary perfusion. By this mechanism, impairment of NO production causes an increase in VE-VCO2 slope. Therefore, changes in VE-VCO2 slope may be regulated by NO production in the pulmonary vessels.

The hypothesis that VE-VCO2 slope is associated with NO was proved in a study by Bocchi et al. [27]. They reported that inhalation of NO attenuated the excessive increase in tidal volume response to exercise and VE-VCO2 slope in patients with CHF and suggested that the L-arginine-NO pathway might be involved in mechanisms contributing to hyperventilation during exercise in CHF.

Peak VO2/HR and cardiac output at peak exercise both correlated positively with peak ETNO. Although the P-value of the correlation between peak cardiac output and peak ETNO was not significant, presumably due to the small sample size, the correlation coefficient was above 0.4, indicating a weak but positive correlation. Since peak VO2/HR is a product of stroke volume and arterial–venous O2 difference, and arterial–venous O2 difference is uniform regardless of the basal disease, peak VO2/HR is assumed to represent cardiac function during exercise. Therefore, diminished peak VO2/HR and cardiac output indicate slowed pulmonary blood flow at peak exercise levels, given no change in arterial–venous O2 difference. Since NO production is stimulated by shear stress, [26] NO production by the pulmonary vessel wall would be attenuated when stroke volume is diminished during exercise. Thus, decreased NO production due to decreased shear stress during exercise may be one mechanism resulting in the increase in the VE-VCO2 slope.

Endothelin-1 and prostacyclin (PGI2) are known to affect endothelial cell function and it has also been reported that these vasoactive substances interact with each other [28]. In this study, we did not investigate the role of these substances. Therefore, it cannot be ruled out that exercise capacity is primarily correlated with ET-1 or PGI2 instead of NO. This requires further investigation. The correlation coefficient between ETNO and the VE-VCO2 slope was not strong, as shown in Fig. 1. The reason of this weak correlation may, in part, be due to multi-factorial regulation.

In this study, mean LVEF and peak VO2 were almost within the normal range. This is accounted for by the wide range of functional class in our subjects. Our objective was to determine if there was any association between exercise tolerance, cardiac function and NO exhalation. We found that ETNO was diminished in patients with impaired exercise tolerance.


   5. Conclusion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In conclusion, when NO production is decreased in the pulmonary vascular bed, ventilatory response to exercise increases and exercise tolerance is reduced in patients with heart disease.


   Acknowledgements
 
The authors wish to thank Prof. Karlman Waserman for his kind and useful suggestions, as well as Yasuyuki Kobayashi, Shigeru Tsuchida, Kimiyo Ogawa, Kazumi Maruyama and Kazuhiko Ida for their technical assistance.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
{star} There are no potential conflicts of interest with this paper. Back


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

  1. Sullivan M.J., Higginbotham M.B., Cobb F.R. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation (1988) 77:552–559.[Abstract/Free Full Text]
  2. Metra M., Dei Cas L., Panina G., Visioli O. Exercise hyperventilation chronic congestive heart failure, and its relation to functional capacity and hemodynamics. Am J Cardiol (1992) 70:622–628.[CrossRef][Web of Science][Medline]
  3. Rubin S.A., Brown H.V. Ventilation and gas exchange during exercise in severe chronic heart failure. Am Rev Respir Dis (1984) 129(2 Pt 2):S63–S64.[Web of Science][Medline]
  4. Juratsch C.E., Whipp B.J., Huntsman D.J., Laks M.M., Wasserman K. Ventilatory control during experimental maldistribution of VA/Q in the dog. J Appl Physiol (1982) 52:245–253.[Abstract/Free Full Text]
  5. Wasserman K., Whipp B.J., Casaburi R., Golden M., Beaver W.L. Ventilatory control during exercise in man. Bull Eur Physiopathol Respir (1979) 15:27–51.[Web of Science][Medline]
  6. Palmer R.M.J., Ferrige A.G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature (1987) 327:524–526.[CrossRef][Medline]
  7. Vane J.R., Anggard E.E., Botting M. Regulatory functions of the vascular endothelium. N Engl J Med (1990) 323:27–36.[Web of Science][Medline]
  8. Kubo S.H., Rector T.S., Bank A.J., Williams R.E., Heifetz S.M. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation (1991) 84:1589–1596.[Abstract/Free Full Text]
  9. Adachi H., Nguyen P.H., Belardinelli R., Hunter D., Jung T., Wasserman K. Nitric oxide production during exercise in chronic heart failure. Am Heart J (1997) 133:196–202.
  10. Katz S.D., Khan T., Zeballos G.A., Mathew L., Potharlanka P., Knecht M., et al. Decreased activity of the L-arginine-nitric oxide metabolic pathway in patients with congestive heart failure. Circulation (1999) 99:2113–2117.[Abstract/Free Full Text]
  11. Winlaw D.S., Smythe G.A., Keogh A.M., Schyvens C.G., Spratt P.M., Macdonald P.S. Nitric oxide production and heart failure. Lancet (1995) 345:390–391.[Web of Science][Medline]
  12. Funakoshi T., Yamabe H., Yokoyama M. Increased exhaled nitric oxide and impaired oxygen uptake (VO2) kinetics during exercise in patients with chronic heart failure. Jpn Circ J (1999) 63:255–260.[CrossRef][Medline]
  13. Matsumoto A., Ogura K., Hirata Y., Kakoki M., Watanabe F., Takenaka K., et al. Increased nitric oxide in the exhaled air of patientswith decompensated liver cirrhosis. Ann Intern Med (1995) 123:110–113.[Abstract/Free Full Text]
  14. St Croix C.M., Wetter T.J., Pegelow D.F., Meyer K.C., Dempsey J.A. Assessment of nitric oxide formation during exercise. Am J Respir Crit Care Med (1999) 159(4 Pt 1):1125–1133.[Abstract/Free Full Text]
  15. Wennmalm A., Benthin G., Edlund A., Jungersten L., Kieler-Jensen N., Lundin S., et al. Metabolism and excretion of nitric oxide in humans. An experimental and clinical study. Circ Res (1993) 73:1121–1127.[Abstract/Free Full Text]
  16. Lucke J.N. Determination of the cardiac output of anaesthetised pigs using a dye dilution method. Res Vet Sci (1976) 21:364–365.[Web of Science][Medline]
  17. de Leeuw P.W., Birkenhager W.H. Some comments on the usefulness of measuring cardiac output by dye dilution. Eur Heart J (1990) 11(Suppl. I(4)):13–16.[Abstract/Free Full Text]
  18. Beaver W.L., Wasserman K., Whipp B.J. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol (1986) 60:2020–2027.[Abstract/Free Full Text]
  19. Buller N.P., Poole-Wilson P.A. Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure. Br Heart J (1990) 63:281–283.[Abstract/Free Full Text]
  20. Maroun M.J., Mehta S., Turcotte R., Cosio M.G., Hussain S.N. Effects of physical conditioning on endogenous nitric oxide output during exercise. J Appl Physiol (1995) 79:1219–1225.[Abstract/Free Full Text]
  21. Pogliaghi S., Krasney J.A., Pendergast D.R. Effect of gravity on lung exhaled nitric oxide at rest and during exercise. Respir Physiol (1997) 107:157–164.[CrossRef][Web of Science][Medline]
  22. Bauer J.A., Wald J.A., Doran S., Soda D. Endogenous nitric oxide in expired air: effects of acute exercise in humans. Life Sci (1994) 55:1903–1909.[CrossRef][Web of Science][Medline]
  23. Kharitonov S.A., Barnes P.J. Exhaled markers of pulmonary diseases. Am J Respir Crit Care Med (2001) 163:1693–1722.[Free Full Text]
  24. Lundberg J.O., Weitzberg E., Nordvall S.L., Kuylenstierna R., Lundberg J.M., Alving K. Primarily nasal origin of exhaled nitric oxide and absence in Kartagener's syndrome. Eur Respir J (1994) 7:1501–1504.[Abstract]
  25. Gerlach H., Rossaint R., Pappert D., Knorr M., Falke K.J. Autoinhalation of nitric oxide after endogenous synthesis in nasopharynx. Lancet (1994) 343:518–519.[CrossRef][Web of Science][Medline]
  26. Miller V.M., Aarhus L.L., Vanhoutte P.M. Modulation of endothelium-dependent responses by chronic alterations of blood flow. Am J Physiol (1986) 251(3 Pt 2):H520–H527.[Web of Science][Medline]
  27. Bocchi E.A., Auler J.O. Jr, Guimaraes G.V., Carmona M.J., Wajngarten M., Bellotti G., et al. Nitric oxide inhalation reduces pulmonary tidal volume during exercise in severe chronic heart failure. Am Heart J (1997) 134:737–744.[CrossRef][Web of Science][Medline]
  28. Katz S.D. The role of endothelium-derived vasoactive substances in the pathophysiology of exercise intolerance in patients with congestive heart failure. Prog Cardiovasc Dis (1995) 38:23–50.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 CirculationHome page
S. D. Katz, K. Hryniewicz, I. Hriljac, K. Balidemaj, C. Dimayuga, A. Hudaihed, and A. Yasskiy
Vascular Endothelial Dysfunction and Mortality Risk in Patients With Chronic Heart Failure
Circulation, January 25, 2005; 111(3): 310 - 314.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Adachi, H.
Right arrow Articles by Ito, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Adachi, H.
Right arrow Articles by Ito, H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?