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The Relationship Between Leptin and Ventilatory Control in Heart Failure
Journal of Cardiac Failure Vol. 19 No. 11 2013
The Relationship Between Leptin and Ventilatory Control in Heart Failure IVAN CUNDRLE JR, MD,1,2 VIREND K. SOMERS, MD, PhD,2 PRACHI SINGH, PhD,2 BRUCE D. JOHNSON, PhD,2 CHRISTOPHER G. SCOTT, MS,3 AND LYLE J. OLSON, MD2 Brno, Czech Republic; and Rochester, Minnesota
ABSTRACT Background: Increased serum leptin concentration has been linked to increased ventilation in patients with mild heart failure (HF). However, in animal models the absence of leptin has also been associated with increased ventilation. This study evaluated the relationship of circulating leptin concentration with exercise ventilation in HF patients. Methods and Results: Fifty-eight consecutive ambulatory HF patients were stratified by quintiles of leptin concentration, with a lowest quintile of mean leptin concentration of 1.8 6 8.9 ng/mL and a highest of 33.3 6 30.3 ng/mL. Peak exercise ventilatory efficiency (VE/VCO2) was significantly elevated in the lowest (46 6 6 vs 34 6 4; P ! .01) as well as in the highest (38 6 8 vs 34 6 4; P ! .05) leptin concentration quintiles compared with the reference middle quintile. Multiple regression analysis adjusted for confounders such as age, sex, and body mass index showed leptin concentration to be independently inversely correlated to VE/VCO2 in the low-to-normal quintiles (b 5 0.64; P ! .01), positively in the normal-to-high quintiles (b 5 0.52; P 5 .02), and positively correlated to PETCO2 in the low-tonormal quintiles (b 5 0.59; P 5 .01) and inversely in the normal-to-high quintiles (b 5 0.53; P 5 .02). Conclusions: In HF patients, both high and low leptin concentrations are associated with increased VE/ VCO2 and decreased PETCO2 with a nonlinear U-shaped relationship, suggesting that either leptin deficiency or leptin resistance may modulate ventilatory control in HF patients. (J Cardiac Fail 2013;19:756e761) Key Words: Cardiopulmonary exercise testing, ventilatory efficiency, leptin resistance.
Altered ventilatory control with hyperventilation is frequent in heart failure (HF) patients and associated with more severe symptoms, worse functional capacity,1 and increased mortality.2 Potential causes of hyperventilation
include activation of pulmonary J receptors due to congestion, ventilation-perfusion mismatch, increased activation of central and peripheral chemoreflexes, and the ergoreflex.1 Leptin is an adipokine important for the regulation of food intake and energy expenditure.3 Since its discovery, leptin has emerged as a pleiotropic hormone with versatile functions in the cardiovascular4 and respiratory5 systems. Leptin regulatory function has been extensively studied and proposed as a possible link between metabolic, cardiovascular, and ventilatory abnormalities in HF.6 Earlier investigation has demonstrated that increased circulating leptin concentration is associated with increased minute ventilation per unit of expired carbon dioxide (VE/VCO2) consistent with increased ventilatory drive.6 However, increased ventilatory drive has also been observed in leptin-deficient ob/ob knockout mice5 and is reversed by administration of leptin.7,8 The seemingly disparate observations that the absence of leptin in ob/ob knockout mice and elevated leptin concentration in human HF promote increased ventilatory drive suggest that either lack of leptin or leptin resistance may be responsible. By definition, leptin resistance requires the presence of increased serum leptin concentration.9
From the 1International Clinical Research Center, Department of Anesthesiology and Intensive Care, St. Anna’s University Hospital, Brno, Czech Republic; 2Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota and 3Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota. Manuscript received August 7, 2013; revised manuscript received September 19, 2013; revised manuscript accepted October 11, 2013. Reprint requests: Lyle J. Olson, MD, Professor of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Tel: 507-284-1648; Fax: 507-266-0228. E-mail: olson.lyle@ mayo.edu Funding: European Regional Development FundeProject FNUSA-ICRC (no. CZ.1.05/1.1.00/02.0123), European Social Fund and the State Budget of the Czech Republic, Mayo Foundation, American Heart Association (04-50103Z), National Heart Lung and Blood Institute (HL65176), and National Center for Research Resources (1ULI RR024150). See page 760 for disclosure information. 1071-9164/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2013.10.004
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Leptin and Ventilation in Heart Failure
Resistance to the metabolic effects of leptin has been previously described in obese patients.10 Studies of ventilatory control in obese patients have also been consistent with the presence of leptin resistance.11 We hypothesized that the relationship of leptin concentration with exercise ventilation is nonlinear in HF patients and that either leptin deficiency or high leptin serum concentrations are associated with increased ventilatory drive. Accordingly, the aim of this study was to evaluate the relationship of serum leptin concentration with exercise ventilation measured in HF patients. Methods Subject Selection Subjects were consecutive ambulatory outpatients evaluated in the Mayo Heart Failure Clinic with left ventricular ejection fraction (LVEF) #35% and stable HF symptoms (New York Heart Association [NYHA] functional class IeIV) on optimized pharmacotherapy.12 Clinical stability was defined as no symptom progression and no hospitalization or adjustment of HF therapy in the 3 months preceding enrollment. Exclusion criteria were known sleep apnea or inability to perform cardiopulmonary exercise testing. Each of the participants gave written informed consent after being provided a description of study requirements. The investigation conformed to the principles outlined in the Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board. All procedures followed institutional and Health Insurance Portability and Accountability Act guidelines. Exercise Testing Functional capacity was assessed by cardiopulmonary exercise testing to volitional fatigue following instrumentation for the measurement of heart rate, metabolic gas exchange, and oxygen saturation. The protocol used an initial treadmill speed and grade of 2.0 miles per hour and 0%, respectively, with speed and grade increased every 2 minutes to yield a w2 metabolic equivalent increase per work level to a rating of perceived exertion of 18e20 on the Borg scale. Exercise ventilation and gas exchange were assessed by metabolic cart (Medical Graphics, St Paul, Minnesota) during cardiopulmonary exercise testing. Measures included peak oxygen consumption, carbon dioxide output, partial pressure of end-tidal carbon dioxide (PETCO2), tidal volume, minute ventilation, and breathing frequency. These data were collected continuously and reported as averages obtained over the final 30 seconds of each workload. Derived measures included the ventilatory efficiency defined as the VE/VCO2 ratio. The VE/VCO2 ratio has been shown to strongly correlate to the VE/VCO2 slope1 and may be used to describe ventilatory efficiency at different stages of exercise as well as at rest. Leptin, Natriuretic Peptides, and Echocardiography Venous blood for B-type natriuretic peptide (BNP) and leptin was collected and measured on the same day as cardiopulmonary exercise testing with the use of commercially available kits. Measurement of plasma leptin was performed with the use of radioimmunoassay (Linco Research, St Charles, Missouri; intraand interassay variabilities 3.4%e8.3% and 3.6%e6.2%, respectively). Measurement of BNP was evaluated by either the Shionogi
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immunoradiometric assay (Shionogi and Co, Osaka, Japan) or DxI 800 immunoassay (Beckman Instruments, Chaska, Minnesota). The coefficient of variation of these latter 2 BNP assays was O0.99. Echocardiography measurements were performed with a focus on cardiac chamber dimensions, LVEF, and stroke volume index. Statistical Analysis For the evaluation of normally distributed data, the ShapiroWilk test was used. Subjects were divided into quintiles according to leptin concentration. One-way analysis of variance was used to test for differences among the quintiles, and an unpaired t test or Mann-Whitney U test was used to compare the subject variables between the reference quintile (3rd) and remaining quintiles. Logarithmic transformation was performed for variables with nonnormal distribution. Multiple regression analysis (after controlling for potential confounders such as sex, age, body mass index [BMI], and LVEF) was used to assess the relationship between log leptin concentration and other variables. The results were expressed as the beta coefficient, F ratio, and P value. Data are summarized as mean 6 SD; P values of !.05 were considered to be statistically significant. Statistical analyses were performed with the use of Statistica 10.0 (Statsoft, Prague, Czech Republic) and the Statistical Analysis System (SAS Institute, Cary, North Carolina).
Results Fifty-eight HF patients were included in the analysis. Subjects were mostly men (74%), with NYHA functional class III status (57%), low LVEF, low peak exercise oxygen consumption, and high BNP (Table 1). For the entire group, leptin concentration was independently positively correlated with BMI (b 5 0.52; F 5 27; P ! .01) and inversely with BNP (b 5 0.27; F 5 26; P 5 .01) and VE/VCO2 (b 5 0.20; F 5 24; P 5 .03). For further comparison, subjects were divided into quintiles according to leptin concentration. The middle (3rd) quintile, with the nearest to physiologic leptin concentration (10.8 6 2.3 ng/mL), was considered as the reference,13 and the 1st quintile included subjects with the lowest (1.8 6 0.9 ng/mL) and the 5th quintile subjects with the highest (33.3 6 10.3 ng/mL) mean leptin concentrations. Comparison of the clinical characteristics among quintiles is presented in Table 2. When compared with the reference Table 1. Clinical Characteristics (n 5 58) Age, y Male, n (%) BMI, kg/m2 NYHA I/II/III/IV, n (%) SVI, mL/m2 (n 5 57) LVEF, % peak VO2/kg, mL/kg peak VE/VCO2 BNP, ng/L Leptin, ng/mL
65 6 10 43 (74%) 28 6 5 14 (24)/9 (16)/33 (57)/2 (3) 40 6 11 26 6 9 15.7 6 4.7 39 6 8 660 6 804 13.4 6 11.8
BMI, body mass index; NYHA, New York Heart Association functional class; SVI, stroke volume index; LVEF, left ventricular ejection fraction; VO2, oxygen consumption; VE/VCO2, exercise ventilatory efficiency; BNP, B-type natriuretic peptide.
758 Journal of Cardiac Failure Vol. 19 No. 11 November 2013 Table 2. Clinical Characteristics by Leptin Quintile Parameter Male, % Age, y BMI, kg/m2 NYHA SVI, mL/m2 LVEF, % BNP, ng/L Leptin, ng/mL (range)
Quintile 1 (n 5 12)
Quintile 2 (n 5 12)
Quintile 3 (n 5 11)
Quintile 4 (n 5 12)
Quintile 5 (n 5 11)
P Value (ANOVA)
100 63 6 13 24 6 3* 3 6 1* 32 6 12 19 6 7* 1,513 6 1,166* 1.8 6 0.9* (0e3.4)
92 69 6 9 27 6 4y 261 41 6 10 26 6 7y 764 6 743 6.1 6 1.0* (3.5e7.5)
73 66 6 13 29 6 5y 2 6 1y 37 6 7 27 6 8y 396 6 337y 10.8 6 2.3 (7.6e14.4)
75 67 6 8 29 6 4y 261 46 6 4*y 27 6 7y 250 6 341y 16.9 6 1.5* (14.5e18.8)
27y 59 6 7 32 6 6y 3 6 1* 47 6 14y 30 6 14y 326 6 215y 33.3 6 10.3*y (18.9e48.8)
!.01 .21 !.01 .05 !.01 .03 !.01 !.01
ANOVA, analysis of variance; other abbreviations as in Table 1. *P ! .05 (compared with reference 3rd quintile). y P ! .05 (compared with lowest quintile).
quintile, NYHA functional class and BNP were significantly higher and BMI and LVEF were significantly lower in the 1st quintile. NYHA functional class was also significantly higher in the 5th quintile compared with the reference quintile; BMI, stroke volume index, and LVEF were significantly lower and BNP significantly higher in the 1st quintile than in the 5th quintile. Exercise ventilation comparisons are presented in Table 3. Peak exercise VE/VCO2 was significantly higher (Fig. 1) and peak exercise PETCO2 significantly lower (Fig. 2) in the 1st and 5th quintiles compared with the reference quintile. Peak exercise VE/VCO2 was also significantly higher and peak exercise PETCO2 significantly lower in the 1st quintile than in the 5th quintile. Multiple regression analysis adjusted for gender, age, BMI and LVEF was performed for both exercise variables with bimodal distribution (VE/VCO2 and PETCO2) and separately for lowenormal (1st to 3rd) and normalehigh (3rd to 5th) leptin concentration quintiles (Table 4). In the low to normal quintiles, VE/VCO2 was independently negatively correlated with leptin concentration and
positively with BNP level and NYHA functional class. In contrast, in the normal to high quintiles VE/VCO2 independently positively correlated with BNP level, NYHA functional class, and leptin concentration. PETCO2 was also independently positively correlated with leptin and inversely with BNP level and NYHA functional class in the low to normal quintiles, and in the normal to high quintiles PETCO2 was inversely correlated with leptin concentration. Discussion The major novel finding of this study is that the relationship of serum leptin concentration with exercise ventilation in HF patients is nonlinear and U-shaped. Low leptin concentrations were significantly inversely and high leptin concentrations significantly positively correlated with increased ventilatory drive as demonstrated by elevated peak exercise VE/VCO2 and decreased PETCO2. We suggest that the negative correlation observed in subjects with low leptin levels is a consequence of leptin deficiency,
Table 3. Exercise Parameters by Leptin Quintile Parameter Rest VO2, mL/min/kg VE, L/min VT, mL fb, bpm PETCO2, mm Hg VE/VCO2 Peak exercise VO2, mL/min/kg VE, L/min VT, mL fb, bpm PETCO2, mm Hg VE/VCO2
Quintile 1 (n 5 12)
Quintile 2 (n 5 12)
Quintile 3 (n 5 11)
Quintile 4 (n 5 12)
Quintile 5 (n 5 11)
P Value
3.4 10 564 18 31 50
6 6 6 6 6 6
0.9 3* 144 3 4 9*
4.3 15 710 22 31 48
6 6 6 6 6 6
1.4 5y 194 6* 3 13
4.3 13 870 17 34 41
6 6 6 6 6 6
0.7 5 462 5 4 5y
4.2 13 737 18 35 41
6 6 6 6 6 6
0.7 3y 192 5 5y 5y
3.6 11 718 16 33 40
6 6 6 6 6 6
1.2 4 239 5 3 3y
.08 .04 .12 .03 .04 .02
14.4 50 1696 32 28 46
6 6 6 6 6 6
5.2 22 641 8 7* 9*
15.3 59 1736 34 30 41
6 6 6 6 6 6
4.2 19 424 9 6* 10
17.1 51 1794 31 35 34
6 6 6 6 6 6
3.7 26 781 8 4y 6y
18.2 61 1605 34 35 36
6 6 6 6 6 6
6.0 15 702 8 5y 7y
13.3 49 1493 33 31 38
6 6 6 6 6 6
2.2 12 431 5 4*y 5*y
.07 .28 .73 .76 !.01 .01
bpm, breaths per minute; CSA, central sleep apnea; fb, breathing frequency; PETCO2, partial pressure of end-tidal carbon dioxide; VE, minute ventilation; VT, tidal volume; other abbreviations as in Table 1. *P ! .05 (compared with reference 3rd quintile). y P ! .05 (compared with lowest 1st quintile).
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Table 4. Multiple Regression Analysis 1ste3rd Quintiles
Peak exercise VE/VCO2 Leptin BNP NYHA SVI Peak exercise PETCO2 Leptin BNP NYHA SVI
Fig. 1. Peak exercise ventilatory efficiency by quintiles. Peak exercise ventilatory efficiency (VE/VCO2) was significantly higher in the 1st and 5th quintiles compared with the reference 3rd quintile, demonstrating a U-shaped relationship.
whereas the positive correlation of leptin concentration to ventilatory drive in subjects with high leptin levels is due to leptin resistance. In addition, leptin concentration positively correlated with BMI and inversely with BNP concentration, suggesting a potential role of leptin in the BNP obesity paradox of HF patients.14 The relationship of leptin and ventilatory drive in HF patients has been previously reported by Wolk et al,6 who observed elevated VE/VCO2 to be associated with increased leptin concentration. We also observed a significant positive correlation of leptin concentration and VE/ VCO2 in subjects in the normal to high leptin quintiles, and our subjects in those quintiles were very similar regarding clinical characteristics and exercise ventilation to those individuals described in that earlier study.
Fig. 2. Peak exercise end-tidal carbon dioxide pressure by quintiles. Peak exercise end-tidal carbon dioxide pressure (PETCO2) was significantly lower in the 1st and 5th quintiles compared with the reference 3rd quintile, demonstrating an inverse U-shaped relationship.
3rde5th Quintiles
b
F
P Value
b
F
P Value
0.64 0.61 0.58 0.29
4.2 5 5.9 2.5
!.01 !.01 !.01 .15
0.52 0.38 0.49 0.16
3.2 2.9 3.7 1.9
.02 .04 .01 .37
0.59 0.56 0.52 0.34
3.6 4.2 4.7 2.6
.01 !.01 !.01 .08
0.53 0.35 0.33 0.11
3.1 2.6 2.4 1.7
.02 .07 .09 .54
1st3rd Quintiles, low to normal leptin concentrations; 3rde5th Quintiles, normal to high leptin concentrations; abbreviations as in Tables 1 and 3.
We also observed a significant and independent inverse correlation of leptin concentration and VE/VCO2 in our subjects with low leptin concentration, consistent with the ob/ob knockout mouse model. These mice, lacking leptin, exhibit increased breathing frequency and minute ventilation before the onset of obesity,5 which is prevented by leptin replacement.7 However, the ob/ob knockout mice are eucapnic or hypercapnic with decreased carbon dioxide chemosensitivity.7,8 In contrast, heightened carbon dioxide chemosensitivity is a frequent finding in HF patients,1 and we suggest that the low PETCO2 observed in our subjects may be due to the combined effects of increased carbon dioxide chemosensitivity, leptin deficiency, and lean body habitus. The positive correlation of leptin and ventilatory drive observed by Wolk et al6 and in our subjects in the higher leptin concentration quintiles may be accounted for by leptin resistance. Resistance to the metabolic effects of leptin has been described in obese patients.10 The existence of leptin resistance for the respiratory system has been proposed by O’Donnell et al15 in an animal model and by others in obese patients11 and in obese patients with obstructive sleep apnea.16 Leptin has been shown to have potentially beneficial as well as adverse effects in the cardiovascular system.17 Based on our observations, either the lack of leptin or the relative lack of leptin (ie, leptin resistance) promotes increased VE/VCO2. Elevated VE/VCO2 has been found to be associated with increased morbidity and adverse prognosis in HF patients.2 It has been suggested that the association between serum leptin concentration and VE/VCO2 may contribute, in part, to the adverse prognostic implications of increased VE/VCO2.6 In the present study, the proportion of women increased with the increase of leptin concentration. This is consistent with earlier reports which have demonstrated that women have significantly higher leptin concentrations.18 It has been shown that healthy women have significantly lower PETCO2 and higher VE/VCO2,19 and in women with HF
760 Journal of Cardiac Failure Vol. 19 No. 11 November 2013 VE/VCO2 has been shown to be higher than in men.20 Notably, the serum leptin concentration and VE/VCO2 or PETCO2 relationship observed in the present study was significant even after controlling for sex. In this study, circulating leptin concentration was also independently inversely correlated with BNP concentration. Our observations are consistent with earlier in vitro21 and rodent studies22 which have shown that natriuretic peptides decrease leptin release from adipocytes. Furthermore, BNP has been recently found to act as a strong lipolytic factor,23 which promotes cardiac cachexia,24 and lowers total body fat and leptin production.25 However, increased leptin has also been found to decrease natriuretic peptide concentrations,22 suggesting that leptin and natriuretic peptides may be counter-regulatory. The mechanism of the BNP obesity paradox has not yet been elucidated.14 The positive correlation of serum leptin concentration and BMI in the present study is consistent with earlier reports26 and, taken together with the observation of an inverse correlation between leptin and BNP concentrations, suggests that increased leptin in obese patients with HF may promote decreased BNP.27 Further mechanistic studies are needed to clarify this potential relationship. A limitation of the present study was that we did not analyze concentrations of the soluble leptin receptor which may provide additional insight into the relationship of leptin concentrations to ventilation.6 Stratification to quintiles allowed us to demonstrate the ‘‘U-shaped’’ relationship of leptin and ventilatory drive (VE/VCO2 and PETCO2). However, it also produced smaller groups for statistical comparison, which could have caused overestimation of the significance of our findings. In mitigation, the strength of our study lies in the study population encompassing the entire clinical spectrum for both circulating leptin concentration and severity of HF. Another statistical limitation was that the multiple regression analysis was adjusted for BMI, which may underestimate the proportion of body fat.28 We did not estimate the percentage of body fat and so were unable to include this measure in the analysis. However, it has been shown that both BMI and the percentage of body fat strongly correlate with leptin concentrations.26 In conclusion, in HF patients either high or low leptin concentrations are associated with increased VE/VCO2 and decreased PETCO2, demonstrating a nonlinear U-shaped relationship that may be caused by either deficient leptin or leptin resistance and which may modulate ventilatory control. Increased circulating leptin levels may also contribute to the low BNP concentrations observed in HF patients with high BMI and promote the obesity paradox of HF. Disclosures Dr Somers has served as a consultant for Resmed, Cardiac Concepts, Glaxo Smith Kline, Sepracor, Deshum, Respicardia, and Medtronic and has been a principal investigator or coinvestigator on research grants funded
by Respironics Foundation, Resmed Foundation, and Sorin. All of the other authors have no potential conflict of interest to disclose.
References 1. Woods PR, Olson TP, Frantz RP, Johnson BD. Causes of breathing inefficiency during exercise in heart failure. J Card Fail 2010;16:835e42. 2. Arena R, Myers J, Aslam SS, Varughese EB, Peberdy MA. Peak VO2 and VE/VCO2 slope in patients with heart failure: a prognostic comparison. Am Heart J 2004;147:354e60. 3. Osborn O, Sanchez-Alavez M, Brownell SE, Ross B, Klaus J, Dubins J, et al. Metabolic characterization of a mouse deficient in all known leptin receptor isoforms. Cell Mol Neurobiol 2010;30:23e33. 4. Karmazyn M, Purdham DM, Rajapurohitam V, Zeidan A. Leptin as a cardiac hypertrophic factor: a potential target for therapeutics. Trends Cardiovasc Med 2007;17:206e11. 5. Malli F, Papaioannou AI, Gourgoulianis KI, Daniil Z. The role of leptin in the respiratory system: an overview. Respir Res 2010;11:152. 6. Wolk R, Johnson BD, Somers VK. Leptin and the ventilatory response to exercise in heart failure. J Am Coll Cardiol 2003;42:1644e9. 7. Tankersley CG, O’Donnell C, Daood MJ, Watchko JF, Mitzner W, Schwartz A, et al. Leptin attenuates respiratory complications associated with the obese phenotype. J Appl Physiol 1985 1998;85:2261e9. 8. Tankersley C, Kleeberger S, Russ B, Schwartz A, Smith P. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol 1996;81:716e23. 9. Martin SS, Qasim A, Reilly MP. Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol 2008;52:1201e10. 10. Schwartz MW, Prigeon RL, Kahn SE, Nicolson M, Moore J, Morawiecki A, et al. Evidence that plasma leptin and insulin levels are associated with body adiposity via different mechanisms. Diabetes Care 1997;20:1476e81. 11. Campo A, Fr€uhbeck G, Zulueta JJ, Iriarte J, Seijo LM, Alcaide AB, et al. Hyperleptinaemia, respiratory drive and hypercapnic response in obese patients. Eur Respir J 2007;30:223e31. 12. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG, 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;53:1343e82. 13. Wolk R, Deb A, Caplice NM, Somers VK. Leptin receptor and functional effects of leptin in human endothelial progenitor cells. Atherosclerosis 2005;183:131e9. 14. Clerico A, Giannoni A, Vittorini S, Emdin M. The paradox of low BNP levels in obesity. Heart Fail Rev 2012;17:81e96. 15. O’Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG, Schwartz AR, et al. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med 1999;159:1477e84. 16. Shimura R, Tatsumi K, Nakamura A, Kasahara Y, Tanabe N, Takiguchi Y, et al. Fat accumulation, leptin, and hypercapnia in obstructive sleep apnea-hypopnea syndrome. Chest 2005;127:543e9. 17. Wolk R, Somers VK. Leptin and vascular function: friend or foe? Eur Heart J 2006;27:2263e5. 18. Couillard C, Mauriege P, Prud’homme D, Nadeau A, Tremblay A, Bouchard C, et al. Plasma leptin concentrations: gender differences and associations with metabolic risk factors for cardiovascular disease. Diabetologia 1997;40:1178e84. 19. Aitken ML, Franklin JL, Pierson DJ, Schoene RB. Influence of body size and gender on control of ventilation. J Appl Physiol 1986;60:1894e9. 20. Guazzi M, Arena R, Myers J. Comparison of the prognostic value of cardiopulmonary exercise testing between male and female patients with heart failure. Int J Cardiol 2006;113:395e400.
Leptin and Ventilation in Heart Failure 21. 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;65:1883e8. 22. Yuan K, Yu J, Shah A, Gao S, Kim SY, Kim SZ, et al. Leptin reduces plasma ANP level via nitric oxide-dependent mechanism. Am J Physiol Regul Integr Comp Physiol 2010;298:R1007e16. 23. Polak J, Kotrc M, Wedellova Z, Jabor A, Malek I, Kautzner J, et al. Lipolytic effects of B-type natriuretic peptide 1e32 in adipose tissue of heart failure patients compared with healthy controls. J Am Coll Cardiol 2011;58:1119e25. 24. Costello-Boerrigter LC, Burnett JC. A new role for the natriuretic peptides: metabolic regulators of the adipocyte. JAm Coll Cardiol 2009;53:2078e9.
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25. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009;89: 381e410. 26. Ruhl CE, Harris TB, Ding J, Goodpaster BH, Kanaya AM, Kritchevsky SB, et al. Body mass index and serum leptin concentration independently estimate percentage body fat in older adults. Am J Clin Nutr 2007;85:1121e6. 27. Horwich TB, Hamilton MA, Fonarow GC. B-Type Natriuretic peptide levels in obese patients with advanced heart failure. J Am Coll Cardiol 2006;47:85e90. 28. Shah NR, Braverman ER. Measuring adiposity in patients: the utility of body mass index (BMI), percent body fat, and leptin. PLoS One 2012;7:e33308.
The Relationship Between Leptin and Ventilatory Control in Heart Failure IVAN CUNDRLE JR, MD,1,2 VIREND K. SOMERS, MD, PhD,2 PRACHI SINGH, PhD,2 BRUCE D. JOHNSON, PhD,2 CHRISTOPHER G. SCOTT, MS,3 AND LYLE J. OLSON, MD2 Brno, Czech Republic; and Rochester, Minnesota
ABSTRACT Background: Increased serum leptin concentration has been linked to increased ventilation in patients with mild heart failure (HF). However, in animal models the absence of leptin has also been associated with increased ventilation. This study evaluated the relationship of circulating leptin concentration with exercise ventilation in HF patients. Methods and Results: Fifty-eight consecutive ambulatory HF patients were stratified by quintiles of leptin concentration, with a lowest quintile of mean leptin concentration of 1.8 6 8.9 ng/mL and a highest of 33.3 6 30.3 ng/mL. Peak exercise ventilatory efficiency (VE/VCO2) was significantly elevated in the lowest (46 6 6 vs 34 6 4; P ! .01) as well as in the highest (38 6 8 vs 34 6 4; P ! .05) leptin concentration quintiles compared with the reference middle quintile. Multiple regression analysis adjusted for confounders such as age, sex, and body mass index showed leptin concentration to be independently inversely correlated to VE/VCO2 in the low-to-normal quintiles (b 5 0.64; P ! .01), positively in the normal-to-high quintiles (b 5 0.52; P 5 .02), and positively correlated to PETCO2 in the low-tonormal quintiles (b 5 0.59; P 5 .01) and inversely in the normal-to-high quintiles (b 5 0.53; P 5 .02). Conclusions: In HF patients, both high and low leptin concentrations are associated with increased VE/ VCO2 and decreased PETCO2 with a nonlinear U-shaped relationship, suggesting that either leptin deficiency or leptin resistance may modulate ventilatory control in HF patients. (J Cardiac Fail 2013;19:756e761) Key Words: Cardiopulmonary exercise testing, ventilatory efficiency, leptin resistance.
Altered ventilatory control with hyperventilation is frequent in heart failure (HF) patients and associated with more severe symptoms, worse functional capacity,1 and increased mortality.2 Potential causes of hyperventilation
include activation of pulmonary J receptors due to congestion, ventilation-perfusion mismatch, increased activation of central and peripheral chemoreflexes, and the ergoreflex.1 Leptin is an adipokine important for the regulation of food intake and energy expenditure.3 Since its discovery, leptin has emerged as a pleiotropic hormone with versatile functions in the cardiovascular4 and respiratory5 systems. Leptin regulatory function has been extensively studied and proposed as a possible link between metabolic, cardiovascular, and ventilatory abnormalities in HF.6 Earlier investigation has demonstrated that increased circulating leptin concentration is associated with increased minute ventilation per unit of expired carbon dioxide (VE/VCO2) consistent with increased ventilatory drive.6 However, increased ventilatory drive has also been observed in leptin-deficient ob/ob knockout mice5 and is reversed by administration of leptin.7,8 The seemingly disparate observations that the absence of leptin in ob/ob knockout mice and elevated leptin concentration in human HF promote increased ventilatory drive suggest that either lack of leptin or leptin resistance may be responsible. By definition, leptin resistance requires the presence of increased serum leptin concentration.9
From the 1International Clinical Research Center, Department of Anesthesiology and Intensive Care, St. Anna’s University Hospital, Brno, Czech Republic; 2Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota and 3Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota. Manuscript received August 7, 2013; revised manuscript received September 19, 2013; revised manuscript accepted October 11, 2013. Reprint requests: Lyle J. Olson, MD, Professor of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Tel: 507-284-1648; Fax: 507-266-0228. E-mail: olson.lyle@ mayo.edu Funding: European Regional Development FundeProject FNUSA-ICRC (no. CZ.1.05/1.1.00/02.0123), European Social Fund and the State Budget of the Czech Republic, Mayo Foundation, American Heart Association (04-50103Z), National Heart Lung and Blood Institute (HL65176), and National Center for Research Resources (1ULI RR024150). See page 760 for disclosure information. 1071-9164/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2013.10.004
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Leptin and Ventilation in Heart Failure
Resistance to the metabolic effects of leptin has been previously described in obese patients.10 Studies of ventilatory control in obese patients have also been consistent with the presence of leptin resistance.11 We hypothesized that the relationship of leptin concentration with exercise ventilation is nonlinear in HF patients and that either leptin deficiency or high leptin serum concentrations are associated with increased ventilatory drive. Accordingly, the aim of this study was to evaluate the relationship of serum leptin concentration with exercise ventilation measured in HF patients. Methods Subject Selection Subjects were consecutive ambulatory outpatients evaluated in the Mayo Heart Failure Clinic with left ventricular ejection fraction (LVEF) #35% and stable HF symptoms (New York Heart Association [NYHA] functional class IeIV) on optimized pharmacotherapy.12 Clinical stability was defined as no symptom progression and no hospitalization or adjustment of HF therapy in the 3 months preceding enrollment. Exclusion criteria were known sleep apnea or inability to perform cardiopulmonary exercise testing. Each of the participants gave written informed consent after being provided a description of study requirements. The investigation conformed to the principles outlined in the Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board. All procedures followed institutional and Health Insurance Portability and Accountability Act guidelines. Exercise Testing Functional capacity was assessed by cardiopulmonary exercise testing to volitional fatigue following instrumentation for the measurement of heart rate, metabolic gas exchange, and oxygen saturation. The protocol used an initial treadmill speed and grade of 2.0 miles per hour and 0%, respectively, with speed and grade increased every 2 minutes to yield a w2 metabolic equivalent increase per work level to a rating of perceived exertion of 18e20 on the Borg scale. Exercise ventilation and gas exchange were assessed by metabolic cart (Medical Graphics, St Paul, Minnesota) during cardiopulmonary exercise testing. Measures included peak oxygen consumption, carbon dioxide output, partial pressure of end-tidal carbon dioxide (PETCO2), tidal volume, minute ventilation, and breathing frequency. These data were collected continuously and reported as averages obtained over the final 30 seconds of each workload. Derived measures included the ventilatory efficiency defined as the VE/VCO2 ratio. The VE/VCO2 ratio has been shown to strongly correlate to the VE/VCO2 slope1 and may be used to describe ventilatory efficiency at different stages of exercise as well as at rest. Leptin, Natriuretic Peptides, and Echocardiography Venous blood for B-type natriuretic peptide (BNP) and leptin was collected and measured on the same day as cardiopulmonary exercise testing with the use of commercially available kits. Measurement of plasma leptin was performed with the use of radioimmunoassay (Linco Research, St Charles, Missouri; intraand interassay variabilities 3.4%e8.3% and 3.6%e6.2%, respectively). Measurement of BNP was evaluated by either the Shionogi
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immunoradiometric assay (Shionogi and Co, Osaka, Japan) or DxI 800 immunoassay (Beckman Instruments, Chaska, Minnesota). The coefficient of variation of these latter 2 BNP assays was O0.99. Echocardiography measurements were performed with a focus on cardiac chamber dimensions, LVEF, and stroke volume index. Statistical Analysis For the evaluation of normally distributed data, the ShapiroWilk test was used. Subjects were divided into quintiles according to leptin concentration. One-way analysis of variance was used to test for differences among the quintiles, and an unpaired t test or Mann-Whitney U test was used to compare the subject variables between the reference quintile (3rd) and remaining quintiles. Logarithmic transformation was performed for variables with nonnormal distribution. Multiple regression analysis (after controlling for potential confounders such as sex, age, body mass index [BMI], and LVEF) was used to assess the relationship between log leptin concentration and other variables. The results were expressed as the beta coefficient, F ratio, and P value. Data are summarized as mean 6 SD; P values of !.05 were considered to be statistically significant. Statistical analyses were performed with the use of Statistica 10.0 (Statsoft, Prague, Czech Republic) and the Statistical Analysis System (SAS Institute, Cary, North Carolina).
Results Fifty-eight HF patients were included in the analysis. Subjects were mostly men (74%), with NYHA functional class III status (57%), low LVEF, low peak exercise oxygen consumption, and high BNP (Table 1). For the entire group, leptin concentration was independently positively correlated with BMI (b 5 0.52; F 5 27; P ! .01) and inversely with BNP (b 5 0.27; F 5 26; P 5 .01) and VE/VCO2 (b 5 0.20; F 5 24; P 5 .03). For further comparison, subjects were divided into quintiles according to leptin concentration. The middle (3rd) quintile, with the nearest to physiologic leptin concentration (10.8 6 2.3 ng/mL), was considered as the reference,13 and the 1st quintile included subjects with the lowest (1.8 6 0.9 ng/mL) and the 5th quintile subjects with the highest (33.3 6 10.3 ng/mL) mean leptin concentrations. Comparison of the clinical characteristics among quintiles is presented in Table 2. When compared with the reference Table 1. Clinical Characteristics (n 5 58) Age, y Male, n (%) BMI, kg/m2 NYHA I/II/III/IV, n (%) SVI, mL/m2 (n 5 57) LVEF, % peak VO2/kg, mL/kg peak VE/VCO2 BNP, ng/L Leptin, ng/mL
65 6 10 43 (74%) 28 6 5 14 (24)/9 (16)/33 (57)/2 (3) 40 6 11 26 6 9 15.7 6 4.7 39 6 8 660 6 804 13.4 6 11.8
BMI, body mass index; NYHA, New York Heart Association functional class; SVI, stroke volume index; LVEF, left ventricular ejection fraction; VO2, oxygen consumption; VE/VCO2, exercise ventilatory efficiency; BNP, B-type natriuretic peptide.
758 Journal of Cardiac Failure Vol. 19 No. 11 November 2013 Table 2. Clinical Characteristics by Leptin Quintile Parameter Male, % Age, y BMI, kg/m2 NYHA SVI, mL/m2 LVEF, % BNP, ng/L Leptin, ng/mL (range)
Quintile 1 (n 5 12)
Quintile 2 (n 5 12)
Quintile 3 (n 5 11)
Quintile 4 (n 5 12)
Quintile 5 (n 5 11)
P Value (ANOVA)
100 63 6 13 24 6 3* 3 6 1* 32 6 12 19 6 7* 1,513 6 1,166* 1.8 6 0.9* (0e3.4)
92 69 6 9 27 6 4y 261 41 6 10 26 6 7y 764 6 743 6.1 6 1.0* (3.5e7.5)
73 66 6 13 29 6 5y 2 6 1y 37 6 7 27 6 8y 396 6 337y 10.8 6 2.3 (7.6e14.4)
75 67 6 8 29 6 4y 261 46 6 4*y 27 6 7y 250 6 341y 16.9 6 1.5* (14.5e18.8)
27y 59 6 7 32 6 6y 3 6 1* 47 6 14y 30 6 14y 326 6 215y 33.3 6 10.3*y (18.9e48.8)
!.01 .21 !.01 .05 !.01 .03 !.01 !.01
ANOVA, analysis of variance; other abbreviations as in Table 1. *P ! .05 (compared with reference 3rd quintile). y P ! .05 (compared with lowest quintile).
quintile, NYHA functional class and BNP were significantly higher and BMI and LVEF were significantly lower in the 1st quintile. NYHA functional class was also significantly higher in the 5th quintile compared with the reference quintile; BMI, stroke volume index, and LVEF were significantly lower and BNP significantly higher in the 1st quintile than in the 5th quintile. Exercise ventilation comparisons are presented in Table 3. Peak exercise VE/VCO2 was significantly higher (Fig. 1) and peak exercise PETCO2 significantly lower (Fig. 2) in the 1st and 5th quintiles compared with the reference quintile. Peak exercise VE/VCO2 was also significantly higher and peak exercise PETCO2 significantly lower in the 1st quintile than in the 5th quintile. Multiple regression analysis adjusted for gender, age, BMI and LVEF was performed for both exercise variables with bimodal distribution (VE/VCO2 and PETCO2) and separately for lowenormal (1st to 3rd) and normalehigh (3rd to 5th) leptin concentration quintiles (Table 4). In the low to normal quintiles, VE/VCO2 was independently negatively correlated with leptin concentration and
positively with BNP level and NYHA functional class. In contrast, in the normal to high quintiles VE/VCO2 independently positively correlated with BNP level, NYHA functional class, and leptin concentration. PETCO2 was also independently positively correlated with leptin and inversely with BNP level and NYHA functional class in the low to normal quintiles, and in the normal to high quintiles PETCO2 was inversely correlated with leptin concentration. Discussion The major novel finding of this study is that the relationship of serum leptin concentration with exercise ventilation in HF patients is nonlinear and U-shaped. Low leptin concentrations were significantly inversely and high leptin concentrations significantly positively correlated with increased ventilatory drive as demonstrated by elevated peak exercise VE/VCO2 and decreased PETCO2. We suggest that the negative correlation observed in subjects with low leptin levels is a consequence of leptin deficiency,
Table 3. Exercise Parameters by Leptin Quintile Parameter Rest VO2, mL/min/kg VE, L/min VT, mL fb, bpm PETCO2, mm Hg VE/VCO2 Peak exercise VO2, mL/min/kg VE, L/min VT, mL fb, bpm PETCO2, mm Hg VE/VCO2
Quintile 1 (n 5 12)
Quintile 2 (n 5 12)
Quintile 3 (n 5 11)
Quintile 4 (n 5 12)
Quintile 5 (n 5 11)
P Value
3.4 10 564 18 31 50
6 6 6 6 6 6
0.9 3* 144 3 4 9*
4.3 15 710 22 31 48
6 6 6 6 6 6
1.4 5y 194 6* 3 13
4.3 13 870 17 34 41
6 6 6 6 6 6
0.7 5 462 5 4 5y
4.2 13 737 18 35 41
6 6 6 6 6 6
0.7 3y 192 5 5y 5y
3.6 11 718 16 33 40
6 6 6 6 6 6
1.2 4 239 5 3 3y
.08 .04 .12 .03 .04 .02
14.4 50 1696 32 28 46
6 6 6 6 6 6
5.2 22 641 8 7* 9*
15.3 59 1736 34 30 41
6 6 6 6 6 6
4.2 19 424 9 6* 10
17.1 51 1794 31 35 34
6 6 6 6 6 6
3.7 26 781 8 4y 6y
18.2 61 1605 34 35 36
6 6 6 6 6 6
6.0 15 702 8 5y 7y
13.3 49 1493 33 31 38
6 6 6 6 6 6
2.2 12 431 5 4*y 5*y
.07 .28 .73 .76 !.01 .01
bpm, breaths per minute; CSA, central sleep apnea; fb, breathing frequency; PETCO2, partial pressure of end-tidal carbon dioxide; VE, minute ventilation; VT, tidal volume; other abbreviations as in Table 1. *P ! .05 (compared with reference 3rd quintile). y P ! .05 (compared with lowest 1st quintile).
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Table 4. Multiple Regression Analysis 1ste3rd Quintiles
Peak exercise VE/VCO2 Leptin BNP NYHA SVI Peak exercise PETCO2 Leptin BNP NYHA SVI
Fig. 1. Peak exercise ventilatory efficiency by quintiles. Peak exercise ventilatory efficiency (VE/VCO2) was significantly higher in the 1st and 5th quintiles compared with the reference 3rd quintile, demonstrating a U-shaped relationship.
whereas the positive correlation of leptin concentration to ventilatory drive in subjects with high leptin levels is due to leptin resistance. In addition, leptin concentration positively correlated with BMI and inversely with BNP concentration, suggesting a potential role of leptin in the BNP obesity paradox of HF patients.14 The relationship of leptin and ventilatory drive in HF patients has been previously reported by Wolk et al,6 who observed elevated VE/VCO2 to be associated with increased leptin concentration. We also observed a significant positive correlation of leptin concentration and VE/ VCO2 in subjects in the normal to high leptin quintiles, and our subjects in those quintiles were very similar regarding clinical characteristics and exercise ventilation to those individuals described in that earlier study.
Fig. 2. Peak exercise end-tidal carbon dioxide pressure by quintiles. Peak exercise end-tidal carbon dioxide pressure (PETCO2) was significantly lower in the 1st and 5th quintiles compared with the reference 3rd quintile, demonstrating an inverse U-shaped relationship.
3rde5th Quintiles
b
F
P Value
b
F
P Value
0.64 0.61 0.58 0.29
4.2 5 5.9 2.5
!.01 !.01 !.01 .15
0.52 0.38 0.49 0.16
3.2 2.9 3.7 1.9
.02 .04 .01 .37
0.59 0.56 0.52 0.34
3.6 4.2 4.7 2.6
.01 !.01 !.01 .08
0.53 0.35 0.33 0.11
3.1 2.6 2.4 1.7
.02 .07 .09 .54
1st3rd Quintiles, low to normal leptin concentrations; 3rde5th Quintiles, normal to high leptin concentrations; abbreviations as in Tables 1 and 3.
We also observed a significant and independent inverse correlation of leptin concentration and VE/VCO2 in our subjects with low leptin concentration, consistent with the ob/ob knockout mouse model. These mice, lacking leptin, exhibit increased breathing frequency and minute ventilation before the onset of obesity,5 which is prevented by leptin replacement.7 However, the ob/ob knockout mice are eucapnic or hypercapnic with decreased carbon dioxide chemosensitivity.7,8 In contrast, heightened carbon dioxide chemosensitivity is a frequent finding in HF patients,1 and we suggest that the low PETCO2 observed in our subjects may be due to the combined effects of increased carbon dioxide chemosensitivity, leptin deficiency, and lean body habitus. The positive correlation of leptin and ventilatory drive observed by Wolk et al6 and in our subjects in the higher leptin concentration quintiles may be accounted for by leptin resistance. Resistance to the metabolic effects of leptin has been described in obese patients.10 The existence of leptin resistance for the respiratory system has been proposed by O’Donnell et al15 in an animal model and by others in obese patients11 and in obese patients with obstructive sleep apnea.16 Leptin has been shown to have potentially beneficial as well as adverse effects in the cardiovascular system.17 Based on our observations, either the lack of leptin or the relative lack of leptin (ie, leptin resistance) promotes increased VE/VCO2. Elevated VE/VCO2 has been found to be associated with increased morbidity and adverse prognosis in HF patients.2 It has been suggested that the association between serum leptin concentration and VE/VCO2 may contribute, in part, to the adverse prognostic implications of increased VE/VCO2.6 In the present study, the proportion of women increased with the increase of leptin concentration. This is consistent with earlier reports which have demonstrated that women have significantly higher leptin concentrations.18 It has been shown that healthy women have significantly lower PETCO2 and higher VE/VCO2,19 and in women with HF
760 Journal of Cardiac Failure Vol. 19 No. 11 November 2013 VE/VCO2 has been shown to be higher than in men.20 Notably, the serum leptin concentration and VE/VCO2 or PETCO2 relationship observed in the present study was significant even after controlling for sex. In this study, circulating leptin concentration was also independently inversely correlated with BNP concentration. Our observations are consistent with earlier in vitro21 and rodent studies22 which have shown that natriuretic peptides decrease leptin release from adipocytes. Furthermore, BNP has been recently found to act as a strong lipolytic factor,23 which promotes cardiac cachexia,24 and lowers total body fat and leptin production.25 However, increased leptin has also been found to decrease natriuretic peptide concentrations,22 suggesting that leptin and natriuretic peptides may be counter-regulatory. The mechanism of the BNP obesity paradox has not yet been elucidated.14 The positive correlation of serum leptin concentration and BMI in the present study is consistent with earlier reports26 and, taken together with the observation of an inverse correlation between leptin and BNP concentrations, suggests that increased leptin in obese patients with HF may promote decreased BNP.27 Further mechanistic studies are needed to clarify this potential relationship. A limitation of the present study was that we did not analyze concentrations of the soluble leptin receptor which may provide additional insight into the relationship of leptin concentrations to ventilation.6 Stratification to quintiles allowed us to demonstrate the ‘‘U-shaped’’ relationship of leptin and ventilatory drive (VE/VCO2 and PETCO2). However, it also produced smaller groups for statistical comparison, which could have caused overestimation of the significance of our findings. In mitigation, the strength of our study lies in the study population encompassing the entire clinical spectrum for both circulating leptin concentration and severity of HF. Another statistical limitation was that the multiple regression analysis was adjusted for BMI, which may underestimate the proportion of body fat.28 We did not estimate the percentage of body fat and so were unable to include this measure in the analysis. However, it has been shown that both BMI and the percentage of body fat strongly correlate with leptin concentrations.26 In conclusion, in HF patients either high or low leptin concentrations are associated with increased VE/VCO2 and decreased PETCO2, demonstrating a nonlinear U-shaped relationship that may be caused by either deficient leptin or leptin resistance and which may modulate ventilatory control. Increased circulating leptin levels may also contribute to the low BNP concentrations observed in HF patients with high BMI and promote the obesity paradox of HF. Disclosures Dr Somers has served as a consultant for Resmed, Cardiac Concepts, Glaxo Smith Kline, Sepracor, Deshum, Respicardia, and Medtronic and has been a principal investigator or coinvestigator on research grants funded
by Respironics Foundation, Resmed Foundation, and Sorin. All of the other authors have no potential conflict of interest to disclose.
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Leptin and Ventilation in Heart Failure 21. 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;65:1883e8. 22. Yuan K, Yu J, Shah A, Gao S, Kim SY, Kim SZ, et al. Leptin reduces plasma ANP level via nitric oxide-dependent mechanism. Am J Physiol Regul Integr Comp Physiol 2010;298:R1007e16. 23. Polak J, Kotrc M, Wedellova Z, Jabor A, Malek I, Kautzner J, et al. Lipolytic effects of B-type natriuretic peptide 1e32 in adipose tissue of heart failure patients compared with healthy controls. J Am Coll Cardiol 2011;58:1119e25. 24. Costello-Boerrigter LC, Burnett JC. A new role for the natriuretic peptides: metabolic regulators of the adipocyte. JAm Coll Cardiol 2009;53:2078e9.
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25. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009;89: 381e410. 26. Ruhl CE, Harris TB, Ding J, Goodpaster BH, Kanaya AM, Kritchevsky SB, et al. Body mass index and serum leptin concentration independently estimate percentage body fat in older adults. Am J Clin Nutr 2007;85:1121e6. 27. Horwich TB, Hamilton MA, Fonarow GC. B-Type Natriuretic peptide levels in obese patients with advanced heart failure. J Am Coll Cardiol 2006;47:85e90. 28. Shah NR, Braverman ER. Measuring adiposity in patients: the utility of body mass index (BMI), percent body fat, and leptin. PLoS One 2012;7:e33308.