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J Am Coll Cardiol, 2003; 42:1644-1649, doi:10.1016/j.jacc.2003.06.007
© 2003 by the American College of Cardiology Foundation
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CLINICAL RESEARCH

Leptin and the ventilatory response to exercise in heart failure

Robert Wolk, MD, PhD*, Bruce D. Johnson, PhD* and Virend K. Somers, MD, PhD, FACC*,*

* Mayo Clinic, Rochester, Minnesota, USA

Manuscript received April 18, 2003; revised manuscript received June 3, 2003, accepted June 9, 2003.

* Reprint requests and correspondence: Dr. Virend K. Somers, Mayo Foundation, St. Mary's Hospital, DO-4-350, 1216 Second Street SW, Rochester, Minnesota 55902, USA.
somers.virend{at}mayo.edu


   Abstract
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Methods
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 Discussion
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OBJECTIVES: The aim of the study was to test the hypothesis that leptin is involved in the regulation of ventilatory responses to exercise in chronic heart failure (CHF).

BACKGROUND: Exercise-induced hyperventilation is a negative prognostic factor in CHF. Studies in animals suggest that leptin, a hormone secreted by adipocytes, contributes to the regulation of respiration. Plasma leptin levels are elevated in non-cachectic CHF, suggesting the possibility that leptin might be involved in dysregulation of ventilation in CHF.

METHODS: We studied 50 patients with stable CHF without cachexia. All subjects underwent anthropometric measurements, resting echocardiography, pulmonary function tests, and a cardiopulmonary exercise test. The ventilatory response to exercise was assessed by calculating the VE/VCO2 and VE/VO2 slopes (VE = ventilation per unit time, VCO2 = carbon dioxide production, VO2 = oxygen consumption).

RESULTS: Using a multiple regression model, leptin was significantly and positively correlated with both VE/VCO2 slope (regression coefficient = 0.87, F = 39.32, p < 0.001) and VE/VO2 slope (regression coefficient = 0.84, F = 24.04, p < 0.001). This correlation was independent of age, gender, body mass index, body fat, ejection fraction, New York Heart Association functional class, pulmonary function, plasma norepinephrine, angiotensin II, brain natriuretic peptide levels, and medications. Also, the greatest VE/VCO2 slope was seen in subjects in the highest tertile of leptin.

CONCLUSIONS: Leptin is an independent predictor of VE/VCO2 slope in heart failure, and may be a link between metabolic, cardiovascular, and respiratory abnormalities in CHF.

Abbreviations and Acronyms
  BMI = body mass index
  BNP = brain natriuretic peptide
  CHF = chronic heart failure
  DLCO = diffusion capacity of the lung for carbon monoxide
  EF = ejection fraction
  FEV1 = forced expiratory volume in 1 s
  FVC = forced vital capacity
  NYHA = New York Heart Association
  VCO2 = carbon dioxide production
  VE = ventilation per unit time
  VO2 = oxygen consumption

Leptin is a 167-amino-acid product of the ob gene, which is produced primarily by adipocytes (1). Although originally associated with the central regulation of satiety and energy metabolism, there is now increasing evidence that leptin may be an important mediator in cardiovascular pathophysiology (2–8). In addition, recent studies in animals suggest that leptin may play an important role in the regulation of respiration, particularly the ventilatory responses to CO2, and may act both as a neurohumoral modulator of respiratory control mechanisms as well as by producing changes in respiratory mechanics (9–13).

A growing body of literature has described marked ventilatory abnormalities in response to exercise in chronic heart failure (CHF), including a reduced ventilatory efficiency (a high minute ventilation relative to metabolic demand) (14). Ventilatory efficiency during exercise can be assessed by calculating the VE/VCO2 slope, where VE = ventilation per unit time and VCO2 = carbon dioxide production. Typically, the VE/VCO2 slope is increased in patients with CHF in part due to an enhanced ventilatory drive (15,16). Several recent studies have demonstrated that a hyperventilatory response to exercise is a powerful prognostic factor in CHF (15–19). When combined with reduced peak oxygen consumption (VO2), ventilatory abnormalities identify a subgroup of CHF patients at a particularly high risk of death (16,17,19). Importantly, the VE/VCO2 slope may be a powerful predictor of event-free survival, while peak VO2 does not substantially improve the predictive value of the model (16,18). These latter observations speak to the pathophysiologic significance of the mechanisms regulating ventilatory responses to exercise in patients with CHF.

Most clinical studies have reported elevated circulating leptin levels in non-cachectic CHF (20–24). However, the pathophysiologic role of circulating leptin in CHF remains unknown. In the present study we tested the hypothesis that leptin is involved in the regulation of ventilatory responses to exercise in subjects with CHF.


   Methods
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Fifty consecutively eligible Caucasian patients with a diagnosis of stable non-cachectic systolic CHF were recruited prospectively at the Mayo Clinic, Rochester, Minnesota. Cardiac cachexia was defined as a body weight <85% of ideal (25). The etiology of CHF was ischemic or nonischemic dilated cardiomyopathy. Patients with conditions likely to influence exercise tolerance independent of CHF (primary lung disease, obesity, musculoskeletal diseases, peripheral vascular disease, chest pain, pacemaker dependency, atrial fibrillation), valvular heart disease, history of complex ventricular arrhythmias, or with a moderate smoking history, were excluded. The clinical characteristics of the study group are shown in Table 1. The study was approved by the Mayo Institutional Review Board. Informed consent was obtained before participation.


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  		Table 1 Clinical Characteristics (n = 50)

 
All subjects underwent anthropometric measurements (including assessment of body fat [26]), resting echocardiography, pulmonary function tests, and a cardiopulmonary exercise test.

Left ventricular ejection fraction (EF) was assessed using two-dimensional echocardiography. Pulmonary function measurements were performed at rest and included an assessment of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). A single-breath diffusion capacity of the lung for carbon monoxide (DLCO) was also measured. Spirometry and DLCO data were collected in accordance with the American Thoracic Society standards (27).

Gas exchange was measured during graded treadmill testing to volitional fatigue. The measurements were obtained using a Medical Graphics metabolic cart validated with classical gas collection techniques. An initial treadmill speed and grade of 2 mph and 0%, respectively, were adjusted every 2 min to yield ~2 metabolic equivalent increase per work level. Anaerobic threshold was determined by the V-slope method (28). Peak VO2 was defined as the maximal oxygen uptake during exercise. Because of the recent evidence that the adjustment of peak VO2 to lean body mass increases its prognostic value and allows a more reliable comparison between subjects with variable body mass/fat (because body fat represents metabolically inactive mass) (29), we also measured peak VO2 corrected for lean body mass (lean peak VO2). The VE/VCO2 and VE/VO2 slopes were calculated below the respiratory compensation point using linear regression analysis. The exercise characteristics are shown in Table 2.


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  		Table 2 Exercise Characteristics (n = 50)

 
Blood samples were drawn at rest in a supine position. Plasma norepinephrine was measured using high-performance liquid chromatography (ESA Inc., Chelmsford, Massachusetts) (with inter- and intra-assay variability of 3.4% and 3.1%, respectively) and plasma leptin was measured by radioimmunoassay (Linco Research Inc., St. Charles, Missouri) (intra- and inter-assay variability 3.4% to 8.3% and 3.6% to 6.2%, respectively). Brain natriuretic peptide (BNP) was measured by immunoradiometric assay (Shionogi and Co. Ltd., Osaka, Japan) (inter- and intra-assay variability were both 8%) and angiotensin II was measured using a nonequilibrium assay (Phoenix Pharmaceuticals, Belmont, California) (inter- and intra-assay variations were 13% and 9%, respectively).

Statistical analysis.   In order to assess the independent relationship between leptin and ventilation during exercise, all variables were entered into a multiple stepwise regression model. Peak VO2, VE/VO2 slope, and VE/VCO2 slope were used as dependent variables. Independent variables included age, gender, body mass index (BMI), body fat, waist-to-hip ratio, New York Heart Association (NYHA) functional class, EF, plasma norepinephrine, angiotensin II and BNP levels, % predicted FVC, % predicted FEV1, % predicted DLCO, and leptin. After the initial analysis, medications were added to the model. A value of p ≤ 0.05 was considered significant.


   Results
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Discussion
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In univariate analysis, leptin was related to VE/VCO2 slope (Table 3), VE/VO2 slope (r = 0.49, p < 0.001), and lean peak VO2 (Table 4). Leptin was also positively correlated with female gender (r = 0.37, p = 0.008), BMI (r = 0.51, p < 0.001), and body fat (r = 0.73, p < 0.001), and negatively correlated with % predicted FVC (r = –0.29, p = 0.038), % predicted FEV1 (r = –0.28, p = 0.045), and % predicted DLCO (r = –0.32, p = 0.022). Apart from the correlation with leptin, VE/VCO2 slope was also positively correlated with age, plasma norepinephrine, and BNP, and negatively correlated with the respiratory function tests (Table 3). The VE/VCO2 slope did not correlate with body fat in univariate analysis. However, the relationship between leptin and VE/VCO2 slope was further strengthened when leptin levels were adjusted for body fat (r = 0.50, p < 0.001).


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  		Table 3 Association Between VE/VCO2 Slope and Independent Variables in Univariate and Multivariate Analysis

 

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  		Table 4 Association Between Lean Peak VO2 and Independent Variables in Univariate and Multivariate Analysis.

 
When plasma leptin levels were divided into tertiles, the greatest VE/VCO2 slope was seen in subjects in the highest tertile of leptin (Fig. 1a). In contrast, there was no difference between VE/VCO2 values in patients divided into tertiles of body fat (Fig. 1b).



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  		Figure 1 Relationship between VE/VCO2 slope and nonadjusted leptin levels (a) and body fat (b) divided into tertiles (analysis of variance [ANOVA], followed by Newman-Keuls multiple comparison post-hoc tests). Data are expressed as mean ± SEM. When leptin levels adjusted for body fat were divided into tertiles, the relationship between the adjusted leptin tertiles and VE/VCO2 slope was virtually identical to that between VE/VCO2 slope and unadjusted leptin. VCO2 = carbon dioxide production; VE = ventilation per unit time.

 
In previous publications the threshold value for VE/VCO2 slope of 34 was used and shown to identify CHF patients at an increased risk of death (15,19). In our study seven subjects had VE/VCO2 slopes ≥34. In those subjects leptin levels were higher compared with the rest of the study group, both when expressed in absolute values (18.0 ± 10.7 ng/ml vs. 10.3 ± 7.6 ng/ml; p = 0.022) and when expressed as leptin-to-body fat ratio (0.60 ± 0.32 vs. 0.34 ± 0.20; p = 0.004).

In multivariate analysis, leptin was no longer associated with lean peak VO2 (Table 4), but remained significantly correlated with both VE/VCO2 slope (Table 3) and VE/VO2 slope (regression coefficient = 0.84, F = 24.04, p < 0.001). The positive correlation between leptin and ventilatory responses to exercise was independent of age, gender, NYHA functional class, BMI, body fat (expressed as % body fat or absolute fat mass), EF, plasma angiotensin II and BNP levels, or resting pulmonary function. Consistent with previous reports (30), VE/VCO2 slope was related to plasma norepinephrine levels, but the association with leptin was independent of norepinephrine. Importantly, VE/VCO2 slope was significantly and independently correlated not only with absolute levels of leptin, but also with leptin adjusted for body fat (regression coefficient = 0.84, F = 38.61, p < 0.001), body weight (regression coefficient = 0.78, F = 29.19, p < 0.001), and BMI (regression coefficient = 0.77, F = 31.58, p < 0.001). It should be noted that in multivariate analysis and independent of leptin levels, body fat was a negative predictor of ventilatory responses to exercise.

When medication (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, beta-blockers, digoxin, and diuretics, each as a separate independent variable) entered the model, leptin was still independently associated with VE/VCO2 slope (beta-coefficient = 0.92, F = 47.83, p < 0.001) and VE/VO2 slope (beta-coefficient = 0.46, F = 18.06, p < 0.001).

We also investigated whether leptin levels were correlated with ventilatory responses during exercise after adding lean peak VO2 (an index of the severity of heart failure) to the model as an independent variable. Although lean peak VO2 was significantly (negatively) correlated with ventilatory responses to exercise in multivariate analysis, leptin still remained an independent predictor of VE/VCO2 slope (beta-coefficient = 0.75, F = 29.64, p < 0.001) and VE/VO2 slope (beta-coefficient = 0.36, F = 9.78, p = 0.003).


   Discussion
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The novel finding of the present study is the independent relationship between plasma leptin levels and ventilatory responses to exercise in non-cachectic patients with CHF. Specifically, we show that there is a positive correlation between resting plasma leptin levels and VE/VCO2 slope during exercise, which cannot be explained on the basis of anthropometric measurements, body fat, EF, peak VO2, other neurohormone levels, pulmonary function tests, or medication. That plasma leptin is not affected by acute exercise (31,32) supports the possibility that leptin levels measured at rest in our study may be directly related to the regulation of ventilation also during exercise.

Leptin circulates not only in its free form, but also in a complexed form, with the soluble leptin receptor being the major leptin-binding protein (33). Therefore, a possible limitation of our study is the fact that we did not measure plasma levels of the soluble leptin receptor. However, the physiologic role of the soluble leptin receptor has not yet been clarified, either in humans or in animal models. On the one hand, it is possible that the circulating leptin receptor binds leptin and acts as an inhibitor of its biologic effects. On the other hand, the soluble leptin receptor may delay leptin clearance in the kidney leading to hyperleptinemia. The bound leptin may then be made available for release and activate leptin responses. In addition, the soluble leptin receptor may play a role in the transport of leptin across the blood-brain barrier, thereby modulating the effects of leptin in the central nervous system. Consistent with this mode of action, an increase in circulating leptin and an increased weight-reducing effect of leptin were both observed in mice overexpressing the soluble leptin receptor (34). Taken together, these observations suggest that, although the soluble leptin receptor may regulate leptin's availability and bioactivity, its actual role is still unknown and it may potentially either increase or decrease the effects of leptin. Further studies are needed to clarify this issue before the measurements of the soluble leptin receptor can be unambiguously interpreted.

The mechanisms underlying enhanced VE/VCO2 slope in CHF are complex and probably multifactorial. Several explanations have been proposed, including abnormalities of pulmonary hemodynamics and increased pulmonary dead space (35–38), ergoreceptor overactivity (39), and abnormalities of ventilatory reflex control (40,41). With respect to the latter mechanism, it has been reported that an abnormally elevated VE/VCO2 slope in CHF correlates with both central and peripheral chemosensitivity (40,41). Interestingly, this relationship was much stronger for central hypercapnic chemosensitivity (40,41). This observation is in agreement with our previous study, which demonstrated a selective potentiation of central chemosensitivity in patients with stable CHF (42).

The effects of leptin on the above mechanisms are essentially unknown. An intriguing possibility is the effect of leptin on ventilatory control. The influence of leptin on pulmonary mechanics (12) seems unlikely as an explanation for our findings, because in our study the effects of leptin were independent of pulmonary function. It is of note, however, that studies in ob/ob mutant mice have demonstrated that leptin is a powerful respiratory stimulant and leptin deficiency is associated with a depressed hypercapnic ventilatory response (9,13). Leptin replacement in animals with respiratory depression and elevated PaCO2 has been shown to reverse hypoventilation, most likely by stimulation of central respiratory control centers (11). These studies in animals are consistent with the observation that chemoreflex sensitivity to CO2 is selectively potentiated in human obesity (a condition known to be associated with elevated leptin levels) (43). Although significant hypercapnia is not usually seen during exercise, this does not exclude the presence of increased chemosensitivity, whereby a given CO2 level would constitute a stronger ventilatory stimulus. Nevertheless, other mechanisms underlying the association between leptin and ventilation during exercise may also be important and require further studies.

Although age, female gender, norepinephrine, BNP, leptin, and body fat were all associated with VE/VCO2 slope in multivariate analysis, leptin and body fat were by far the most powerful predictors. The strong negative association between body fat (whether expressed as % body fat or fat mass) with ventilation during exercise is of interest. This association was independent of leptin, BMI, or fat distribution, and opposite to the effects of leptin (Table 3), suggesting that body fat (perhaps through some other, as yet unidentified mechanisms) exerts an inhibitory and leptin-independent influence on ventilation during exercise. The benchmark clinical studies, which established the relationship between VE/VCO2 slope and prognosis in heart failure, did not take body fat into account (15–19). Our results showing an inverse correlation between body fat and VE/VCO2 slope, after adjusting for leptin, are consistent with emerging data suggesting an inverse relationship between indices of obesity and clinical outcome in patients with heart failure (44–46).

Leptin has been recently shown to be an independent risk factor for coronary heart disease (47). Elevated VE/VCO2 slope is an important predictor of prognosis in CHF (15–19). The association between leptin and VE/VCO2 slope may thus conceivably contribute, at least in part, to the negative prognostic associations of increased VE/VCO2 slope. Our findings suggest a novel concept in heart failure pathophysiology, namely that leptin, independent of obesity, may be a link between metabolic, cardiovascular, and respiratory abnormalities in CHF.


   Acknowledgments
 
The investigators would like to thank Kathy O'Malley and Angela Tarara for their technical assistance regarding the study.


   Footnotes
 
This study was supported by the Mayo Foundation, the Dana Foundation NIH M01-RR00585, HL61560, HL65176, HL70302, HL71478.


   References
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 Abstract
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 References
 

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432[CrossRef][Medline]
  2. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 1997;100:270–278[Medline]
  3. Snitker S, Pratley RE, Nicolson M, Tataranni PA, Ravussin E. Relationship between muscle sympathetic nerve activity and plasma leptin concentration. Obes Res. 1997;5:338–340[Medline]
  4. Lembo G, Vecchione C, Fratta L, et al. Leptin induces direct vasodilation through distinct endothelial mechanisms. Diabetes. 2000;49:293–297[Abstract]
  5. Monroe MB, Van Pelt RE, Schiller BC, Seals DR, Jones PP. Relation of leptin and insulin to adiposity-associated elevations in sympathetic activity with age in humans. Int J Obes Relat Metab Disord. 2000;24:1183–1187[CrossRef][Medline]
  6. Narkiewicz K, Kato M, Phillips BG, et al. Leptin interacts with heart rate but not sympathetic nerve traffic in healthy male subjects. J Hypertens. 2001;19:1089–1094[CrossRef][Medline]
  7. Winnicki M, Phillips BG, Accurso V, et al. Independent association between plasma leptin levels and heart rate in heart transplant recipients. Circulation. 2001;104:384–386[Abstract/Free Full Text]
  8. Quehenberger P, Exner M, Sunder-Plassmann R, et al. Leptin induces endothelin-1 in endothelial cells in vitro. Circ Res. 2002;90:711–718[Abstract/Free Full Text]
  9. Tankersley C, Kleeberger S, Russ B, Schwartz A, Smith P. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol. 1996;81:716–723[Abstract/Free Full Text]
  10. Tankersley CG, O'Donnell C, Daood MJ, et al. Leptin attenuates respiratory complications associated with the obese phenotype. J Appl Physiol. 1998;85:2261–2269[Abstract/Free Full Text]
  11. O'Donnell CP, Schaub CD, Haines AS, et al. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med. 1999;159:1477–1484[Abstract/Free Full Text]
  12. O'Donnell CP, Tankersley CG, Polotsky VP, Schwartz AR, Smith PL. Leptin, obesity, and respiratory function. Respir Physiol. 2000;119:163–170[CrossRef][Medline]
  13. Polotsky VY, Wilson JA, Smaldone MC, et al. Female gender exacerbates respiratory depression in leptin-deficient obesity. Am J Respir Crit Care Med. 2001;164:1470–1475[Abstract/Free Full Text]
  14. Lauer MS, Snader CE. Using exercise testing to prognosticate patients with heart failure. Which parameter should we measure? Cardiol Clin. 2001;19:573–581[CrossRef][Medline]
  15. Chua TP, Ponikowski P, Harrington D, et al. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1997;29:1585–1590[Abstract]
  16. Robbins M, Francis G, Pashkow FJ, et al. Ventilatory and heart rate responses to exercise: better predictors of heart failure mortality than peak oxygen consumption. Circulation. 1999;100:2411–2417[Abstract/Free Full Text]
  17. MacGowan GA, Janosko K, Cecchetti A, Murali S. Exercise-related ventilatory abnormalities and survival in congestive heart failure. Am J Cardiol. 1997;79:1264–1266[CrossRef][Medline]
  18. Kleber FX, Vietzke G, Wernecke KD, et al. Impairment of ventilatory efficiency in heart failure: prognostic impact. Circulation. 2000;101:2803–2809[Abstract/Free Full Text]
  19. Gitt AK, Wasserman K, Kilkowski C, et al. Exercise anaerobic threshold and ventilatory efficiency identify heart failure patients for high risk of early death. Circulation. 2002;106:3079–3084[Abstract/Free Full Text]
  20. Leyva F, Anker SD, Egerer K, Stevenson JC, Kox WJ, Coats AJ. Hyperleptinaemia in chronic heart failure. Relationships with insulin. Eur Heart J. 1998;19:1547–1551[Abstract/Free Full Text]
  21. Bottner A, Eisenhofer G, Friberg P, Rundqvist B, Bornstein SR. Hyperleptinaemia does not correlate with plasma catecholamine levels in chronic heart failure. Eur Heart J. 1999;20:1051–1052 (letter)[Free Full Text]
  22. Doehner W, Pflaum CD, Rauchhaus M, et al. Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia. Eur J Endocrinol. 2001;145:727–735[Abstract]
  23. Filippatos GS, Tsilias K, Venetsanou K, et al. Leptin serum levels in cachectic heart failure patients. Relationship with tumor necrosis factor-alpha system. Int J Cardiol. 2000;76:117–122[CrossRef][Medline]
  24. Christian Schulze P, Kratzsch J, Linke A, et al. Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure. Eur J Heart Fail. 2003;5:33–40[CrossRef][Medline]
  25. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323:236–241[Abstract]
  26. Pollock ML, Schmidt DH, Jackson AS. Measurement of cardiorespiratory fitness and body composition in the clinical setting. Compr Ther. 1980;6:12–27[Medline]
  27. American Thoracic Society. Standardization of spirometry, 1994 update. Am J Resp Crit Care Med. 1995;152:1107–1136[Medline]
  28. Wasserman K, Beaver WL, Whipp BJ. Gas exchange theory and the lactic acidosis (anaerobic) threshold. Circulation. 1990;81(Suppl 1):II14, II30
  29. Osman AF, Mehra MR, Lavie CJ, Nunez E, Milani RV. The incremental prognostic importance of body fat adjusted peak oxygen consumption in chronic heart failure. J Am Coll Cardiol. 2000;36:2126–2131[Abstract/Free Full Text]
  30. Kinugawa T, Tomikura Y, Ogino K, et al. Relation between neurohormonal activation and enhanced ventilatory response to exercise in patients with chronic congestive heart failure. Am J Cardiol. 2002;89:604–607[Medline]
  31. Perusse L, Collier G, Gagnon J, et al. Acute and chronic effects of exercise on leptin levels in humans. J Appl Physiol. 1997;83:5–10[Abstract/Free Full Text]
  32. Weltman A, Pritzlaff CJ, Wideman L, et al. Intensity of acute exercise does not affect serum leptin concentrations in young men. Med Sci Sports Exerc. 2000;32:1556–1561[Medline]
  33. Lammert A, Kiess W, Bottner A, Glasow A, Kratzsch J. Soluble leptin receptor represents the main leptin binding activity in human blood. Biochem Biophys Res Commun. 2001;283:982–988[CrossRef][Medline]
  34. Huang L, Wang Z, Li C. Modulation of circulating leptin levels by its soluble receptor. J Biol Chem. 2001;276:6343–6349[Abstract/Free Full Text]
  35. Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation. 1988;77:552–559[Abstract/Free Full Text]
  36. Metra M, Dei Cas L, Panina G, Visioli O. Exercise hyperventilation chronic congestive heart failure, and its relation to functional capacity and hemodynamics. Am J Cardiol. 1992;70:622–628[CrossRef][Medline]
  37. Wada O, Asanoi H, Miyagi K, et al. Importance of abnormal lung perfusion in excessive exercise ventilation in chronic heart failure. Am Heart J. 1993;125:790–798[CrossRef][Medline]
  38. Reindl I, Wernecke KD, Opitz C, et al. Impaired ventilatory efficiency in chronic heart failure: possible role of pulmonary vasoconstriction. Am Heart J. 1998;136:778–785[CrossRef][Medline]
  39. Ponikowski PP, Chua TP, Francis DP, Capucci A, Coats AJ, Piepoli MF. Muscle ergoreceptor overactivity reflects deterioration in clinical status and cardiorespiratory reflex control in chronic heart failure. Circulation. 2001;104:2324–2330[Abstract/Free Full Text]
  40. Chua TP, Clark AL, Amadi AA, Coats AJ. Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1996;27:650–657[Abstract]
  41. Ponikowski P, Francis DP, Piepoli MF, et al. Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis. Circulation. 2001;103:967–972[Abstract/Free Full Text]
  42. Narkiewicz K, Pesek CA, van de Borne PJ, Kato M, Somers VK. Enhanced sympathetic and ventilatory responses to central chemoreflex activation in heart failure. Circulation. 1999;100:262–267[Abstract/Free Full Text]
  43. Narkiewicz K, Kato M, Pesek CA, Somers VK. Human obesity is characterized by a selective potentiation of central chemoreflex sensitivity. Hypertension. 1999;33:1153–1158[Abstract/Free Full Text]
  44. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, Tillisch JH. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol. 2001;38:789–795[Abstract/Free Full Text]
  45. Mosterd A, Cost B, Hoes AW, et al. The prognosis of heart failure in the general population: the Rotterdam Study. Eur Heart J. 2001;22:1318–1327[Abstract/Free Full Text]
  46. Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol. 2003;91:891–894[CrossRef][Medline]
  47. Wallace AM, McMahon AD, Packard CJ, et al. Plasma leptin and the risk of cardiovascular disease in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 2001;104:3052–3056[Abstract/Free Full Text]



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