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Ivan Cundrle, Jr, MD, PhD; Prachi Singh, PhD; Bruce D. Johnson, PhD; Christopher G. Scott, MS; Lyle J. Olson, MD
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From the Department of Anesthesiology and Intensive Care (Dr Cundrle), International Clinical Research Center, St. Anna’s University Hospital; and the Division of Cardiovascular Diseases (Drs Singh, Johnson, and Olson) and the Department of Biomedical Statistics and Informatics (Mr. Scott), Mayo Clinic.

CORRESPONDENCE TO: Lyle J. Olson, MD, Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: olson.lyle@mayo.edu


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):e198. doi:10.1378/chest.15-0326
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To the Editor:

We appreciate the comments of Drs Javaheri and Schwartz about our article in CHEST.1 Our study was observational, and, as such, we cannot comment on causality regarding leptin and ventilatory drive. Furthermore, caution seems indicated when extrapolating findings from ob/ob mice to human heart failure (HF). First, ob/ob mice are primarily a model of obesity, whereas chronic HF is frequently associated with cachexia. Second, leptin has been shown to influence lung development,2 which may affect ob/ob mice but not patients with HF who experience leptin deficiency only in adulthood. Third, in knock-out animal models, compensatory mechanisms may alter normal physiologic controls and thereby not produce the expected effects of gene deletion.

Tankersley et al2 showed that leptin-deficient ob/ob mice exhibited normal tidal volume but higher breathing frequency, minute ventilation, and ventilatory drive (consistent with hyperventilation) compared with both wild-type and leptin-treated ob/ob mice.2 The increased ventilation was attributable to weight gain, but only in part. Unfortunately, Paco2 was not reported2 but was found to be elevated in ob/ob mice in a subsequent study, suggesting hypoventilation.3 However, in this later study, the minute ventilation of ob/ob mice was again increased (compared with control mice),3 whereas age, obesity, tidal volume, and breathing frequency were even greater than in ob/ob mice from the earlier study. Hence, the ventilation of ob/ob mice was increased, although perhaps insufficiently to compensate for the markedly increased metabolic production of CO2 also characteristic of this model.3

We agree that acute leptin administration stimulates ob/ob mice to increase tidal volume.3 However, acute leptin administration to wild-type mice has no ventilatory effect.3

Interestingly, if wild-type mice are overfed and become obese, leptin concentration rises (leptin resistance develops4) and increased ventilation is observed.3 Indeed, in another study we showed not only an inverse, but also a positive association between leptin and ventilatory drive in patients with HF with higher BMI and leptin concentrations.5 One interpretation of this nonlinear “U-shaped” relation is that it is not an increase in leptin concentration per se, but rather, an absolute or relative leptin deficiency (ie, in the presence of leptin resistance) that stimulates ventilation.

We concur that the causes of central sleep apnea (CSA) involve multiple factors that increase ventilatory drive. We suggest that a low leptin concentration may promote elevated ventilatory drive and, in combination with increased CO2 chemosensitivity, may cause the breathing pattern of CSA characterized by ventilatory overshoot.1 Moreover, we believe it unlikely that low leptin reduced ventilation in our subjects with HF and CSA.

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]
 
Tankersley CG, O’Donnell C, Daood MJ, et al. Leptin attenuates respiratory complications associated with the obese phenotype. J Appl Physiol (1985). 1998;85(6):2261-2269. [PubMed]
 
O’donnell CP, Schaub CD, Haines AS, et al. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med. 1999;159(5 pt 1):1477-1484. [CrossRef] [PubMed]
 
Lin S, Thomas TC, Storlien LH, Huang XF. Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int J Obes Relat Metab Disord. 2000;24(5):639-646. [CrossRef] [PubMed]
 
Cundrle I Jr, Somers VK, Singh P, Johnson BD, Scott CG, Olson LJ. The relationship between leptin and ventilatory control in heart failure. J Card Fail. 2013;19(11):756-761. [CrossRef] [PubMed]
 

Figures

Tables

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]
 
Tankersley CG, O’Donnell C, Daood MJ, et al. Leptin attenuates respiratory complications associated with the obese phenotype. J Appl Physiol (1985). 1998;85(6):2261-2269. [PubMed]
 
O’donnell CP, Schaub CD, Haines AS, et al. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med. 1999;159(5 pt 1):1477-1484. [CrossRef] [PubMed]
 
Lin S, Thomas TC, Storlien LH, Huang XF. Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int J Obes Relat Metab Disord. 2000;24(5):639-646. [CrossRef] [PubMed]
 
Cundrle I Jr, Somers VK, Singh P, Johnson BD, Scott CG, Olson LJ. The relationship between leptin and ventilatory control in heart failure. J Card Fail. 2013;19(11):756-761. [CrossRef] [PubMed]
 
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