European Journal of Heart Failure (2009) 11, 789–794 doi:10.1093/eurjhf/hfp088
Ghrelin resistance occurs in severe heart failure and resolves after heart transplantation Lars H. Lund 1*, Jill J. Williams 2,3, Pamela Freda 4, John J. LaManca 5, Thierry H. LeJemtel 6, and Donna M. Mancini 2 1 Section for Heart Failure, Department of Cardiology, Karolinska University Hospital, N305, 171 76 Stockholm, Sweden; 2Division of Cardiology, Columbia University, New York, NY, USA; 3Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY, USA; 4Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; 5Salisbury University, Salisbury, MD, USA; and 6Department of Medicine, Section of Cardiology, Tulane University School of Medicine, New Orleans, LA, USA
Received 21 April 2009; revised 13 May 2009; accepted 14 May 2009; online publish-ahead-of-print 25 June 2009
Aims
Severe heart failure (HF) is often associated with cachexia that reverses post-heart transplantation (HTx) with frequent development of obesity. Ghrelin is a novel appetite-stimulating hormone. The aim was to determine the role of ghrelin in regulating appetite, food intake, and body composition in HF and post-HTx. ..................................................................................................................................................................................... Methods We measured serial ghrelin, hunger sensation, caloric intake, and body composition in 12 HF patients awaiting HTx, 12 patients 12.7 + 8.6 months post-HTx, and 7 controls. Seven of 12 HF patients were followed for longitudinal and results analysis post-HTx. Body mass index was 23.1 + 3.1 in HF and 31.5 + 5.5 post-HTx (P , 0.001). Heart transplantation patients had gained 18.0 + 7.7 kg since HTx. Ghrelin area under the curve between controlled meals (control: 186 + 39; HF: 264 + 71; HTx: 194 + 47 ng min/mL, P , 0.007) was higher in HF, but test meal caloric intake (control: 1185 + 650; HF: 391 + 103; HTx: 831 + 309 kcal, P , 0.008) was lower in HF. The longitudinal analysis confirmed these findings. ..................................................................................................................................................................................... Conclusion Heart failure may be associated with resistance to the appetite-stimulating effects of ghrelin, which may contribute to cachexia. Heart transplantation may be associated with resolution of ghrelin resistance, which may contribute to weight gain. These findings are preliminary and should be confirmed in larger trials.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Ghrelin † Heart failure † Cachexia † Heart transplantation † Weight gain † Appetite
Introduction Cardiac cachexia is well described in severe heart failure (HF).1,2 Heart transplantation (HTx) is associated with weight gain and the frequent development of obesity. Although this weight gain has been attributed to glucocorticoid therapy, it is more dramatic than after other solid organ transplants, despite similar steroid regimens, and also unrelated to steroid dose,3 suggesting that other mechanisms are responsible. Ghrelin is an appetite-stimulating hormone that is released from the stomach in response to fasting and weight loss and is inhibited by food intake.4,5 Ghrelin was originally identified as the endogenous ligand for the growth hormone (GH) secretagogue receptor and partially acts by stimulating GH release.4 Ghrelin receptors are widely distributed in the heart and vessels,6 and its administration may improve left ventricular function, decrease muscle
wasting, and improve exercise capacity in HF.7 In one study, ghrelin was elevated in cachectic HF.8 Ghrelin has not been studied post-HTx. We hypothesized that cachexia in severe HF may be in part due to resistance to the appetite-stimulating and anabolic effects of ghrelin and that weight gain post-HTx may be in part due to resolution of this resistance. Accordingly, we examined the hormonal regulation of appetite, caloric intake, and body composition in HF, HTx, and matched healthy controls.
Methods We performed a cross-sectional study in 12 patients with New York Heart Association functional class IV HF awaiting HTx, 12 patients 12.7 + 8.6 months post-HTx, and 7 control subjects. We then performed a longitudinal study of 7 of 12 HF patients 7.4 + 4.4 months
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2500 g for 15 min at 48C. Plasma was stored at 2708C. Ghrelin was measured by radioimmunoassay (Phoenix Pharmaceuticals, Belmont, USA) and GH was measured by a two-site immunoradiometric assay (Diagnostic Systems Laboratories, Inc., Webster, USA). Continuous variables were compared by one-way analysis of variance. Pair-wise comparisons between cross-sectional groups were done by Fisher’s least significance test. Paired comparisons between longitudinal groups were done by Student’s t-test. Serial data over time were used to calculate area under the curve (AUC) for ghrelin. Ghrelin and GH were plotted against each other and Pearson’s correlation calculated. A P , 0.05 was considered statistically significant. All results are reported as mean + standard deviation.
after HTx. Of the remaining five HF patients, three patients declined repeat testing after HTx, one died before HTx, and one became too ill for HTx. Subjects were age and gender matched. Heart failure and HTx patients were matched by aetiology, and controls were matched by body mass index (BMI) to HTx (Table 1). The protocol complied with the Declaration of Helsinki and was approved by the institutional review board of Columbia University Medical Center, and written informed consent was obtained from all patients. DEXA scanning to analyse body composition was performed with a QDR 4500 A Delphi W densitometer (Hologic Inc., Bedford, USA). Waist circumference was measured in duplicate at the level of the umbilicus. Measurement of resting energy expenditure (REE) and cardiopulmonary exercise testing with measurement of peak oxygen consumption (peak VO2) was performed using a metabolic cart (Medical Graphics, Minneapolis, USA). Subjects reported to the laboratory at 8 a.m. in the fasting state and underwent blood sampling, completed a visual analogue (0 –10) assessing hunger, and then consumed a yoghurt-based breakfast test meal where they were encouraged to eat until absolute satiety. Eating until absolute satiety ensured that post-prandial assessment would not be affected by differences in baseline food intake and satiety. Postprandial serial blood testing and hunger assessment was performed hourly for 5 h. Subjects were then given a lunch meal of regular food of their choosing and were neither encouraged nor dissuaded to eat. Caloric intake at each meal was estimated using computerized software NDS-R 4.05-33 (University of Minnesota, Minneapolis, USA). Blood was collected in chilled EDTA tubes; 2 mL blood was mixed with 0.1 mL aprotonin (for ghrelin but not GH) and centrifuged at
Results Clinical characteristics and medical regimens of the cross-sectional population are summarized in Table 1. Cachexia, defined as nonoedematous weight loss 7.5% over the preceding 6 months,8,9 was present in 7 of 12 HF patients. Heart transplantation patients had gained 18.0 + 7.7 kg over 12.7 + 8.6 months since HTx. The mean prednisone dose in the HTx patients was 6 + 4 mg/day (range 2 –15). The seven HF patients followed longitudinally (Table 3) had similar age, gender, and medical regimens compared with the 12 cross-sectional HTx patients (Table 1). Results of the cross-sectional study are depicted in Table 2. Heart failure had the lowest BMI, total body mass, lean mass,
Table 1 Baseline characteristics of the cross-sectional cohort Group
Control (n 5 7)
HF (n 5 12)
HTx (n 5 12)
P-value (overall)
Age (years)
42 + 14
52 + 16
47 + 18
.0.2
5 (71%) 2 (29%)
10 (83%) 2 (17%)
11 (92%) 1 (8%)
.0.2
BMI (kg/m2)
27.8 + 4.2
23.1 + 3.1
31.5 + 5.5
