BACKGROUND: Leptin-deficient animals hyperventilate. Leptin expression by adipocytes is attenuated by atrial natriuretic peptide (ANP). Increased circulating natriuretic peptides (NPs) are associated with an increased risk of central sleep apnea (CSA). This study tested whether serum leptin concentration is inversely correlated to NP concentration and decreased in patients with heart failure (HF) and CSA. METHODS: Subjects with HF (N = 29) were studied by measuring leptin, NPs, CO2 chemosensitivity (Δminute ventilation [V.e]/Δpartial pressure of end-tidal CO2 [Petco2]), and ventilatory efficiency (V.e/CO2 output [V.co2]) and were classified as CSA or no sleep-disordered breathing by polysomnography. CSA was defined as a central apnea-hypopnea index ≥ 15. The Student t test, Mann-Whitney U test, and logistic regression were used for analysis, and data were summarized as mean ± SD; P < .05 was considered significant. RESULTS: Subjects with CSA had higher ANP and brain natriuretic peptide (BNP) concentrations (P < .05), ΔV.e/ΔPetco2 (2.39 ± 1.03 L/min/mm Hg vs 1.54 ± 0.35 L/min/mm Hg, P = .01), and V.e/V.co2 (43 ± 9 vs 34 ± 7, P < .01) and lower leptin concentrations (8 ± 10.7 ng/mL vs 17.1 ± 8.8 ng/mL, P < .01). Logistic regression analysis (adjusted for age, sex, and BMI) demonstrated leptin (OR = 0.07; 95% CI, 0.01-0.71; P = .04) and BNP (OR = 4.45; 95% CI, 1.1-17.9; P = .05) to be independently associated with CSA. CONCLUSIONS: In patients with HF and CSA, leptin concentration is low and is inversely related to NP concentration. Counterregulatory interactions of leptin and NP may be important in ventilatory control in HF.

Department of Anesthesiology and Intensive Care International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Department of Biomedical Statistics and Informatics Mayo Clinic Rochester MN

Division of Cardiovascular Diseases Mayo Clinic Rochester MN

Chest. 2015 May;147(5):e197-e198. doi: 10.1378/chest.15-0113. PubMed

Chest. 2015 May;147(5):e198. doi: 10.1378/chest.15-0326. PubMed

Zobrazit více v PubMed

Bradley TD, Floras JS. Sleep apnea and heart failure: part II: central sleep apnea. Circulation. 2003;107(13):1822-1826 PubMed

Wolk R, Kara T, Somers VK. Sleep-disordered breathing and cardiovascular disease. Circulation. 2003;108(1):9-12 PubMed

Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation. 1998;97(21):2154-2159 PubMed

Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med. 1999;160(4):1101-1106 PubMed

Wang H, Parker JD, Newton GE, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol. 2007;49(15):1625-1631 PubMed

Naughton MT, Bradley TD. Sleep apnea in congestive heart failure. Clin Chest Med. 1998;19(1):99-113 PubMed

Mansfield D, Kaye DM, Brunner La Rocca H, Solin P, Esler MD, Naughton MT. Raised sympathetic nerve activity in heart failure and central sleep apnea is due to heart failure severity. Circulation. 2003;107(10):1396-1400 PubMed

Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med. 1995;152(2):473-479 PubMed

Carmona-Bernal C, Quintana-Gallego E, Villa-Gil M, Sánchez-Armengol A, Martínez-Martínez A, Capote F. Brain natriuretic peptide in patients with congestive heart failure and central sleep apnea. Chest. 2005;127(5):1667-1673 PubMed

Calvin AD, Somers VK, van der Walt C, Scott CG, Olson LJ. Relation of natriuretic peptide concentrations to central sleep apnea in patients with heart failure. Chest. 2011;140(6):1517-1523 PubMed PMC

Osborn O, Sanchez-Alavez M, Brownell SE, et al. Metabolic characterization of a mouse deficient in all known leptin receptor isoforms. Cell Mol Neurobiol. 2010;30(1):23-33 PubMed PMC

Karmazyn M, Purdham DM, Rajapurohitam V, Zeidan A. Leptin as a cardiac hypertrophic factor: a potential target for therapeutics. Trends Cardiovasc Med. 2007;17(6):206-211 PubMed

Smith CCT, Dixon RA, Wynne AM, et al. Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol. 2010;299(4):H1265-H1270 PubMed PMC

Malli F, Papaioannou AI, Gourgoulianis KI, Daniil Z. The role of leptin in the respiratory system: an overview. Respir Res. 2010;11(1):152. PubMed PMC

Makinodan K, Yoshikawa M, Fukuoka A, et al. Effect of serum leptin levels on hypercapnic ventilatory response in obstructive sleep apnea. Respiration. 2008;75(3):257-264 PubMed

Shimura R, Tatsumi K, Nakamura A, et al. Fat accumulation, leptin, and hypercapnia in obstructive sleep apnea-hypopnea syndrome. Chest. 2005;127(2):543-549 PubMed

Campo A, Frühbeck G, Zulueta JJ, et al. Hyperleptinaemia, respiratory drive and hypercapnic response in obese patients. Eur Respir J. 2007;30(2):223-231 PubMed

Redolfi S, Corda L, La Piana G, Spandrio S, Prometti P, Tantucci C. Long-term non-invasive ventilation increases chemosensitivity and leptin in obesity-hypoventilation syndrome. Respir Med. 2007;101(6):1191-1195 PubMed

Javaheri S. A mechanism of central sleep apnea in patients with heart failure. N Engl J Med. 1999;341(13):949-954 PubMed

Arzt M, Harth M, Luchner A, et al. Enhanced ventilatory response to exercise in patients with chronic heart failure and central sleep apnea. Circulation. 2003;107(15):1998-2003 PubMed

Ribeiro JP. Periodic breathing in heart failure: bridging the gap between the sleep laboratory and the exercise laboratory. Circulation. 2006;113(1):9-10 PubMed

Fain JN, Kanu A, Bahouth SW, Cowan GSM, Lloyd Hiler M. Inhibition of leptin release by atrial natriuretic peptide (ANP) in human adipocytes. Biochem Pharmacol. 2003;65(11):1883-1888 PubMed

Moro C, Klimcakova E, Lolmède K, et al. Atrial natriuretic peptide inhibits the production of adipokines and cytokines linked to inflammation and insulin resistance in human subcutaneous adipose tissue. Diabetologia. 2007;50(5):1038-1047 PubMed

Tankersley CG, O’Donnell C, Daood MJ, et al. Leptin attenuates respiratory complications associated with the obese phenotype. J Appl Physiol. 1998;85(6):2261-2269 PubMed

Jessup M, Abraham WT, Casey DE, et al. 2009 Focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53(15):1343-1382 PubMed

Iber C, Ancoli-Israel S, Chesson A, Quan SF; for the American Academy of Sleep Medicine The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology, and Technical Specifications. 1st ed Westchester, IL: American Academy of Sleep Medicine; 2007

Read DJ. A clinical method for assessing the ventilatory response to carbon dioxide. Australas Ann Med. 1967;16(1):20-32 PubMed

Kirkpatrick JN, Vannan MA, Narula J, Lang RM. Echocardiography in heart failure: applications, utility, and new horizons. J Am Coll Cardiol. 2007;50(5):381-396 PubMed

Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA. 2003;290(14):1906-1914 PubMed

Mannix ET, Farber MO, Aronoff GR, et al. Regulation of atrial natriuretic peptide release in normal humans. J Appl Physiol. 1991;71(4):1340-1345 PubMed

Mascareno E, Beckles D, Dhar-Mascareno M, Siddiqui MAQ. Enhanced hypertrophy in ob/ob mice due to an impairment in expression of atrial natriuretic peptide. Vascul Pharmacol. 2009;51(2-3):198-204 PubMed PMC

Clerico A, Giannoni A, Vittorini S, Emdin M. The paradox of low BNP levels in obesity. Heart Fail Rev. 2012;17(1):81-96 PubMed

Yuan K, Yu J, Shah A, et al. Leptin reduces plasma ANP level via nitric oxide-dependent mechanism. Am J Physiol Regul Integr Comp Physiol. 2010;298(4):R1007-R1016 PubMed

Javaheri S, Corbett WS. Association of low PaCO2 with central sleep apnea and ventricular arrhythmias in ambulatory patients with stable heart failure. Ann Intern Med. 1998;128(3):204-207 PubMed

Tankersley C, Kleeberger S, Russ B, Schwartz A, Smith P. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol. 1996;81(2):716-723 PubMed

Woods PR, Olson TP, Frantz RP, Johnson BD. Causes of breathing inefficiency during exercise in heart failure. J Card Fail. 2010;16(10):835-842 PubMed PMC

Wolk R, Johnson BD, Somers VK. Leptin and the ventilatory response to exercise in heart failure. J Am Coll Cardiol. 2003;42(9):1644-1649 PubMed

Wolk R, Somers VK. Leptin and vascular function: Friend or foe? Eur Heart J. 2006;27(19):2263-2265 PubMed

Zhou XS, Rowley JA, Demirovic F, Diamond MP, Badr MS. Effect of testosterone on the apneic threshold in women during NREM sleep. J Appl Physiol. 2003;94(1):101-107 PubMed

Luukkaa V, Pesonen U, Huhtaniemi I, et al. Inverse correlation between serum testosterone and leptin in men. J Clin Endocrinol Metab. 1998;83(9):3243-3246 PubMed

Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation scientific statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol. 2008;52(8):686-717 PubMed

Low leptin concentration may identify heart failure patients with central sleep apnea

Exercise end-tidal CO2 predicts central sleep apnea in patients with heart failure