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(Circulation. 2005;112:e84.)
© 2005 American Heart Association, Inc.

Correspondence

Letter Regarding the Article by Katz et al, "Vascular Endothelial Dysfunction and Mortality Risk in Patients With Chronic Heart Failure"

Jon Lundberg, MD, PhD

Department of Physiology & Pharmacology, Karolinska Institute, Stockholm, Sweden, Jon.lundberg{at}fyfa.ki.se

Eddie Weitzberg, MD, PhD

Department of Anesthesiology & Intensive Care, Karolinska Hospital, Stockholm, Sweden, Eddie.weitzberg{at}kirurgi.ki.se

To the Editor:

We read with interest the study by Katz and colleagues in a recent issue of Circulation.¹ The authors have measured exhaled NO and a key observation is that a low level of exhaled NO is associated with an increased mortality risk in patients with chronic heart failure. They claim that exhaled NO is a marker of endothelial function.

The authors state that their method is designed to exclude nasopharyngeal sources of NO. We believe, however, that the methodology might not have been effective at excluding nasopharyngeal-derived NO. These sources of NO, if not properly excluded from the exhaled air, complicate estimation of lower airway-derived NO. What Katz and colleagues describe is actually the optimal method to use if one wishes to maximize contribution from the upper airways to exhaled NO. First, a low-resistance valve minimizes the chances for the soft palate to close, thereby leaving the nasal NO compartment open. In the international guidelines for exhaled NO (available since 1997), it is mandatory to exhale against a resistance to force the palate to close, thereby avoiding nasal NO contamination.² The authors cite Phillips et al³ for the method used to exclude nasal NO. In that study, however, nasal NO was excluded by balloon occlusion of the nasopharynx, which was apparently not used by Katz et al. Moreover, the use of a nose-clip makes things even worse, as it effectively forces the accumulated nasal NO to leak down to the nasopharynx. With the method used, a large contribution from nasopharyngeal NO sources is to be expected.^2,4

The authors also report that inhaled aerosolized NG-monomethyl-L-arginine (L-NMMA, an NO synthase inhibitor) has no effect on exhaled NO. This differs from earlier reports using the same or similar NO synthase inhibitors. It is unexpected because the major part of orally exhaled NO comes from the airway wall.⁴

The over all relationship between exhaled NO and endothelial function is very unclear⁵ and until we have methods that adequately can separate all possible sources of exhaled NO, we believe such a relationship should be discussed with great caution.

	References

Top References References

 

1. Katz SD, Hryniewicz K, Hriljac I, Balidemaj K, Dimayuga C, Hudaihed A, Yasskiy A. Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation. 2005; 111: 310–314.[Abstract/Free Full Text]
   
2. Kharitonov S, Alving K, Barnes PJ. Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force. Eur Respir J. 1997; 10: 1683–1693.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Phillips CR, Giraud GD, Holden WE. Exhaled nitric oxide during exercise: site of release and modulation by ventilation and blood flow. J Appl Physiol. 1996; 80: 1865–1871.[Abstract/Free Full Text]
   
4. Lundberg JO, Weitzberg E, Lundberg JM, Alving K. Nitric oxide in exhaled air. Eur Respir J. 1996; 9: 2671–2680.[Abstract]
   
5. Sartori C, Lepori M, Busch T, Duplain H, Hildebrandt W, Bartsch P, Nicod P, Falke KJ, Scherrer U Exhaled nitric oxide does not provide a marker of vascular endothelial function in healthy humans. Am J Respir Crit Care Med. 1999; 160: 879–882.[Abstract/Free Full Text]
   

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Response

Stuart D. Katz, MD; Katarzyna Hryniewicz, MD; Alhakam Hudaihed, MD; Aleksandr Yasskiy, MD

Department of Internal Medicine, Yale University College of Medicine, New Haven, Conn, stuart.katz{at}yale.edu

Ingrid Hriljac, MD; Kujtim Balidemaj, MD; Clarito Dimayuga, MD

Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY

I thank Drs Lundberg and Weitzberg for their interest in our recently published report.¹ Our technique for exhaled nitric oxide determination differs from many previous reports, as our measurements were made at a submaximal work rate adjusted to a minute ventilation of 20 L/min. In preliminary experiments, inhalation of aerosolized l-NG-monomethylarginine decreased exhaled nitric oxide production during submaximal exercise in normal subjects but not in subjects with chronic heart failure. These findings suggest that nasopharyngeal and upper airway sources of nitric oxide did not contaminate our measurements during submaximal exercise in heart failure subjects and are consistent with the findings of Philips and colleagues,² who showed that the effects of nasopharyngeal balloon occlusion on exhaled nitric oxide production were diminished during higher minute ventilation rates in response to exercise. We agree that nitric oxide in expired gases may be derived from cellular sources other than endothelial cells. As discussed in our article,¹ our finding of a significant association between exhaled nitric oxide production during submaximal exercise and mortality may be related to reduced endothelial production of nitric oxide in the pulmonary circulation, but may also be attributable to autonomic, hemodynamic, and pulmonary abnormalities present in this patient population.

	Acknowledgments

 
This work was supported in part by an American Heart Association (Heritage Affiliate) Grant-In-Aid, and National Heart, Lung, and Blood Institute grants HL K24-04024 and HL R01-51433 (Dr Katz).

	References

Top References References

 

1. Katz SD, Hryniewicz K, Hriljac I, Balidemaj K, Dimayuga C, Hudaihed A, Yasskiy A. Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation. 2005; 111: 310–314.[Abstract/Free Full Text]
   
2. Phillips CR, Giraud GD, Holden WE. Exhaled nitric oxide during exercise: site of release and modulation by ventilation and blood flow. J Appl Physiol. 1996; 80: 1865–1871.[Abstract/Free Full Text]
   

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lundberg, J. Articles by Dimayuga, C. Search for Related Content PubMed PubMed Citation Articles by Lundberg, J. Articles by Dimayuga, C. Related Collections Congestive Endothelium/vascular type/nitric oxide