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Leptin and Ventilation in Heart FailureLeptin and Ventilation in Heart Failure FREE TO VIEW

Shahrokh Javaheri, MD, FCCP; Alan Schwartz, MD
Author and Funding Information

From the College of Medicine (Dr Javaheri), University of Cincinnati; and School of Medicine (Dr Schwartz), Johns Hopkins University.

CORRESPONDENCE TO: Shahrokh Javaheri, MD, Emeritus Professor of Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267; e-mail: shahrokhjavaheri@icloud.com


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(5):e197-e198. doi:10.1378/chest.15-0113
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To the Editor:

We read with great interest the article in CHEST (January 2014) by Dr Cundrle et al1 on the relationship between leptin and central sleep apnea (CSA) in patients with heart failure. The mechanisms of CSA are complex and evolving.2 The authors of this article1 report on a novel observation that the serum leptin level is lower in patients with heart failure with reduced ejection (HFrEF) and comorbid CSA, when compared with patients with HFrEF without CSA. Patients with HFrEF and CSA had higher minute ventilation (and consequently a lower end-tidal Pco2) than patients with HFrEF without CSA. Leptin concentration was significantly and positively correlated with end-tidal Pco2 at rest and during exercise. In other words, the higher the leptin level, the higher the Pco2. Given these findings, the authors indicate “that a similar breathing pattern has been observed in leptin-deficient ob/ob knockout mice, which ventilate with significantly higher V. e [minute ventilation], Vt [tidal volume], and breathing frequency compared with wild-type mice and that this is normalized by leptin replacement.”1

The findings by Cundrle et al1 regarding the association between circulating leptin concentration and CSA are intriguing and suggest potential links between leptin and ventilatory control in patients with HFrEF with this disorder. Nevertheless, we should point out some inconsistencies with insights gained from studies on ventilatory control in leptin-deficient mice.

In particular, the authors cited a study3 demonstrating that leptin-deficient animals hyperventilate. They are indeed correct that absolute levels of ventilation were higher in these obese leptin-deficient compared with lean wild-type mice. These leptin-deficient mice, however, were not actually hyperventilating since their Paco2 was significantly elevated compared with their lean wild-type control subjects,4 leading us to conclude that they were in fact hypoventilating rather than hyperventilating. Importantly, the observed “excess” in minute ventilation in the ob/ob mice was simply required to keep up with elevations in metabolic load (CO2 production and oxygen consumption) in obesity. This phenomenon is also observed in human obese subjects who produce much more CO2 than their lean counterparts, yet this normalizes after adjusting for body surface area.5 A similar mechanism accounts for the progressive increases in ventilation that were observed in ob/ob leptin-deficient mice3 as they gained additional weight. Conversely, ventilation is further increased when these mice are treated with leptin,3 a finding attributed to increases in hypercapneic ventilatory responses independent of body weight. In conclusion, studies in mice indicate that leptin is a respiratory stimulant, which increases ventilatory drive, and that hypoventilation of leptin-deficient ob/ob mice is reversed with leptin replacement.

Instead of implicating leptin in the pathogenesis of CSA in HFrEF, Cundrle et al1 might consider an alternative mechanism. It is generally believed that in heart failure, ventilation is increased via vagally-mediated stimulation of pulmonary receptors, a consequence of pulmonary congestion.2 Whatever the mechanism for this novel finding in patients with HFrEF with CSA,1 we believe that leptin deficiency could have actually decreased (rather than stimulated) ventilation. Indeed, observed decreases in leptin concentrations in these patients may have served to mitigate ventilation and may have exerted beneficial effects in patients with HFrEF.

References

Cundrle I Jr, Somers VK, Singh P, et al. Leptin deficiency promotes central sleep apnea in patients with heart failure. Chest. 2014;145(1):72-78. [CrossRef] [PubMed]
 
Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol. 2013;3(1):141-163. [PubMed]
 
Tankersley C, Kleeberger S, Russ B, Schwartz A, Smith P. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol (1985). 1996;81(2):716-723. [PubMed]
 
O’Donnell CP, Schaub CD, Haines AS, et al. Leptin prevents respiratory depression in obesity. A J Respir Crit Care Med. 1999;159(5 pt 1):1477-1484. [CrossRef]
 
Javaheri S, Simbartl LA. Respiratory determinants of diurnal hypercapnia in obesity hypoventilation syndrome. What does weight have to do with it? Ann Am Thorac Soc. 2014;11(6):945-950. [CrossRef] [PubMed]
 

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References

Cundrle I Jr, Somers VK, Singh P, et al. Leptin deficiency promotes central sleep apnea in patients with heart failure. Chest. 2014;145(1):72-78. [CrossRef] [PubMed]
 
Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol. 2013;3(1):141-163. [PubMed]
 
Tankersley C, Kleeberger S, Russ B, Schwartz A, Smith P. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol (1985). 1996;81(2):716-723. [PubMed]
 
O’Donnell CP, Schaub CD, Haines AS, et al. Leptin prevents respiratory depression in obesity. A J Respir Crit Care Med. 1999;159(5 pt 1):1477-1484. [CrossRef]
 
Javaheri S, Simbartl LA. Respiratory determinants of diurnal hypercapnia in obesity hypoventilation syndrome. What does weight have to do with it? Ann Am Thorac Soc. 2014;11(6):945-950. [CrossRef] [PubMed]
 
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