Ghrelin resistance occurs in severe heart failure and resolves after heart transplantation.

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 AND RESULTS: 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 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.

Growth hormone resistance in severe heart failure resolves after cardiac transplantation.

AIMS: Severe heart failure (HF) is associated with cachexia; this is often reversed post cardiac transplantation (HTx) with frequent development of obesity. Growth hormone (GH) resistance is common in HF and may contribute to cachexia. Whether GH resistance resolves post HTx is unknown. We aimed to confirm that HF is associated with GH resistance and to test the hypothesis that GH resistance resolves post HTx. METHODS AND RESULTS: We measured GH, insulin-like growth factor-1 (IGF-1), and body composition in 10 HF patients awaiting HTx, in 18 patients 11 +/- 8 months post HTx, and seven controls. Body mass index was 23.5 +/- 3.2 in HF patients and 29.3 +/- 5.7 post HTx. HTx patients had gained 14 +/- 8 kg since HTx. GH was elevated in HF (control: 0.21 +/- 0.25; HF: 1.13 +/- 1.19; HTx: 0.11 +/- 0.13 ng/mL; P < 0.007), while IGF-1 was higher in HTx (control: 114 +/- 57; HF: 94 +/- 52; HTx: 190 +/- 106 ng/mL; P < 0.02). HTx had higher total body and abdominal fat %. CONCLUSION: GH resistance is present in severe HF and resolves post HTx. These findings should be confirmed through larger trials.

Cardiopulmonary exercise variables in diastolic versus systolic heart failure.

The response to cardiopulmonary exercise (CPX) in patients with heart failure (HF) with normal left ventricular (LV) ejection fractions (EFs) is not well characterized. To determine if CPX testing could distinguish between patients with HF with normal EFs (>50%; i.e., diastolic HF) and those with decreased EFs (> or =50%; i.e., systolic HF), CPX responses were compared between 185 patients with systolic HF (79% men, mean age 62.6 +/- 10.9 years) and 43 with diastolic HF (54% men, mean age 67.4 +/- 9.8 years) enrolled in a phase II multicenter clinical trial. All patients were evaluated with echocardiography and a standardized CPX test as part of the trial. CPX variables, including oxygen uptake at peak exercise (peak VO(2)) and the slope of the ventilation/carbon dioxide production ratio (VE/VCO(2)), were determined and analyzed by core laboratory personnel. Echocardiographic measurements included the LV EF, the E/A ratio, filling time, cavity volumes, right ventricular function, and mitral regurgitation. Patients in the diastolic HF group tended to be older (p <0.08), with more women (p <0.006) and with greater body mass indexes (p <0.02), than those in the systolic HF group. There was no significant difference in the use of beta blockers or the incidence of coronary artery disease. Patients with diastolic HF had decreased E/A ratios (0.9 +/- 0.4 vs 1.4 +/- 1.1, p <0.02, diastolic HF vs systolic HF) and increased filling times (30.4 +/- 3.2 vs 26.5 +/- 4.7 ms, p <0.01, diastolic HF vs systolic HF). No significant differences in peak VO(2) (14.4 +/- 1.9 vs 15.6 +/- 3.2 ml/kg/min, p = 0.06, diastolic HF vs systolic HF) were observed. The VE/VCO(2) ratios for the 2 groups were abnormal and comparable (32 2 +/- 7.5 vs 34.0 +/- 8.3, p = 0.3, diastolic HF vs systolic HF). In conclusion, the CPX response in patients with diastolic HF and systolic HF is markedly abnormal and indistinguishable with regard to peak VO(2) and ventilation despite marked differences in the LV EF.

Effects of posttraumatic stress disorder on cardiovascular stress responses in Gulf War veterans with fatiguing illness.

Abnormal cardiovascular stress responses have been reported in Gulf War veterans with chronic fatigue. However, many of these veterans also suffer from posttraumatic stress disorder (PTSD), which could potentially explain the reported abnormalities. To test this hypothesis, 55 Gulf veterans (GVs) with chronic fatigue syndrome (CFS) or idiopathic chronic fatigue (ICF) were stratified into groups with (N=16) and without (N=39) comorbid PTSD, and were compared to healthy Gulf veterans (N=47) on cardiovascular responses to a series of stressors. The CFS/ICF with PTSD group had lower blood pressure responses to speech and arithmetic tasks, and more precipitous declines and slower recoveries in blood pressure after standing up than the controls. Similar trends in the CF/ICF group without PTSD were not significant, however. Both CFS/ICF groups had blunted increases in peripheral vascular resistance during mental tasks. However, only the veterans with comorbid PTSD had diminished cardiac output responses to the mental stressors and excessive vasodilatory responses to standing. Symptoms of posttraumatic stress were significant predictors of hypotensive postural responses, but only in veterans reporting a significant exposure to wartime stress. We conclude that comorbid PTSD contributes to dysregulation of cardiovascular responses to mental and postural stressors in Gulf veterans with medically unexplained fatiguing illness, and may provide a physiological basis for increased somatic complaints in Gulf veterans with symptoms of posttraumatic stress.

Aerobic capacity of Gulf War veterans with chronic fatigue syndrome.

A large overlap exists between the diagnosis of chronic fatigue syndrome (CFS) and the unexplained symptoms reported by many Gulf War veterans (GV). Previous investigations have reported reduced aerobic capacity in civilians with CFS. The present investigation examined metabolic responses to maximal exercise in GVs with CFS compared with healthy GVs. Cardiorespiratory and metabolic responses were recorded during a maximal exercise test on a cycle ergometer. The groups were not different in any demographic category (p > 0.05) or self-reported physical activity (p > 0.05). No differences were observed between groups for maximal oxygen uptake (28.9 +/- 6.7 mL/kg/min for CFS vs. 30.8 +/- 7.1 mL/kg/min for controls; p = 0.39), heart rate (155.8 +/- 16.1 bpm for CFS vs. 163.3 +/- 14.9 bpm for controls; p = 0.17), exercise time (9.6 +/- 1.5 minutes for CFS vs. 10.2 +/- 1.4 minutes for controls; p = 0.26), or workload achieved (208 +/- 36.7 W for CFS vs. 224 +/- 42.9 W for controls; p = 0.25). Likewise, no differences were observed at submaximal intensities (p > 0.05). Compared with healthy controls, GVs who report multiple medically unexplained symptoms and meet criteria for CFS do not show a decreased exercise capacity. Thus, it does not appear that the pathology of the GVs with CFS includes a deficiency with mobilizing the cardiopulmonary system for strenuous physical effort.

Baroreceptor reflex and integrative stress responses in chronic fatigue syndrome.

OBJECTIVE: Altered cardiovascular responses to mental and postural stressors have been reported in chronic fatigue syndrome (CFS). This study examined whether those findings may involve changes in baroreceptor reflex functioning. METHODS: Chronotropic baroreceptor reflex (by sequential analysis) and cardiovascular stress responses were recorded during postural (5-minute of active standing) and cognitive (speech task) stress testing in patients with CFS grouped into cases with severe (N = 21) or less severe (N = 22) illness, and in 29 matched control subjects. RESULTS: Patients with CFS had a greater decline in baroreceptor reflex sensitivity (BRS) during standing, although only those with severe CFS were significantly different from the controls. Systolic blood pressure declined during standing in the control group but was maintained in the CFS patients. In contrast, the patients with less severe CFS had blunted increases in blood pressure during the speech task, which could not, however, be explained by inadequate inhibition of the baroreceptor reflex, with all groups showing an appropriate reduction in BRS during the task. CONCLUSIONS: These results indicate that in CFS, deficiencies in orthostatic regulation, but not in centrally mediated stress responses, may involve the baroreceptor reflex. This study also suggests that classifying patients with CFS on illness severity may discriminate between patients with abnormalities in peripheral vs. central mechanisms of cardiovascular stress responses.

Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome.

BACKGROUND: Findings indicative of a problem with circulation have been reported in patients with chronic fatigue syndrome (CFS). We examined this possibility by measuring the patient's cardiac output and assessing its relation to presenting symptoms. METHODS: Impedance cardiography and symptom data were collected from 38 patients with CFS grouped into cases with severe (n = 18) and less severe (n = 20) illness and compared with those from 27 matched, sedentary control subjects. RESULTS: The patients with severe CFS had significantly lower stroke volume and cardiac output than the controls and less ill patients. Postexertional fatigue and flu-like symptoms of infection differentiated the patients with severe CFS from those with less severe CFS (88.5% concordance) and were predictive (R2 = 0.46, P < 0.0002) of lower cardiac output. In contrast, neuropsychiatric symptoms showed no specific association with cardiac output. CONCLUSIONS: These results provide a preliminary indication of reduced circulation in patients with severe CFS. Further research is needed to confirm this finding and to define its clinical implications and pathogenetic mechanisms.

Perceived exertion in fatiguing illness: civilians with chronic fatigue syndrome.

PURPOSE: It has been reported that ratings of perceived exertion (RPE) are elevated in chronic fatigue syndrome (CFS). However, methodological limitations have rendered this conclusion suspect. The purpose of the present investigation was to examine RPE during exercise in civilians with CFS by comparing subjects at both absolute exercise stage and relative oxygen consumption reference criteria. METHODS: A sample of 39 civilian females (N = 19 CFS, 34 +/- 7 yr; N = 20 healthy controls, 33 +/- 7 yr) underwent a maximal exercise test on a treadmill. RPE were obtained during the last 15 s of each 3-min stage using Borg's 6-20 scale. RESULTS: There were no significant differences in peak [OV0312]O(2), RER, or RPE. However, controls exercised longer (20.0 +/- 1.1 vs 15.9 +/- 1.1 min, P = 0.01, healthy vs CFS) and had higher peak HR (183 +/- 3 vs 174 +/- 2 bpm, P = 0.03, healthy vs CFS). Civilians with CFS reported higher RPE at stages 3 through 5 compared with controls (F(3,111)= 3.6,P = 0.017). Preexercise fatigue ratings were not a significant predictor of perceived exertion during exercise. There were no group differences (F(1,37)= 1.9, P = 0.17) when RPE were expressed relative to peak [OV0312]O(2). CONCLUSIONS: Our results show that RPE are greater in civilians with CFS when the data are expressed in terms of absolute exercise intensity. However, by examining RPE relative to a common maximum (i.e., peak [OV0312]O(2)) no differences were observed. The findings of the present investigation challenge the notion that RPE are dysregulated in CFS.

Perceived exertion in fatiguing illness: Gulf War veterans with chronic fatigue syndrome.

PURPOSE: It has been reported that ratings of perceived exertion (RPE) are elevated in chronic fatigue syndrome (CFS). We have challenged this notion by examining perceived exertion in civilian females with CFS and expressing the data relative to exercise capacity (%[OV0312]O(2max)). The purpose of the present investigation was to further examine RPE during exercise in a unique population of CFS patients, Gulf veterans (GV). METHODS: Thirty-four GV (N = 15 CFS, 42 +/- 8 yr; N = 19 healthy, 43 +/- 5 yr) performed a maximal exercise test on a cycle ergometer. After a 3-min warm-up, exercise intensity increased by 30 W every minute until exhaustion. RPE were obtained during the last 15 s of each minute using Borg's CR-10 scale. RESULTS: With the exception of peak [OV0312]E, there were no significant differences in any peak exercise variables. Repeated measures ANOVA revealed significantly higher RPE at each power output examined (F(1,32) = 16.4, P < 0.001). Group differences in RPE remained significant when analyzed relative to peak [OV0312]O(2) (F(1,32) = 7.2, P = 0.01). Both group main effects and the interaction were eliminated when self-reported fatigue symptoms were controlled for in the analyses. Power functions for RPE as a function of relative oxygen consumption were not different between groups and were significantly greater than a linear value of 1.0 (1.6 +/- 0.3 for both groups, P < 0.02). CONCLUSIONS: Our results show that RPE are greater in GV with CFS regardless of whether the data were expressed in terms of absolute or relative exercise intensity. However, self-reported fatigue associated with CFS eliminated the group differences. These results suggest that GV with CFS were unique compared with their civilian counterparts. Future research aimed at determining the influence of preexisting fatigue on RPE during exercise is warranted.

A measure of heart rate variability is sensitive to orthostatic challenge in women with chronic fatigue syndrome.

The use of symptoms generated by head up tilt (HUT) is not a useful tool in identifying chronic fatigue syndrome (CFS). We investigated whether heart rate variability (HRV) assessed early during HUT might be useful. A sample of 46 female subjects (24 with CFS and 22 sedentary, age-matched healthy controls; CON) who had exhibited no difference in time to syncope during tilt was examined for HRV responses to 10 min of 70 degrees HUT after 5 min of baseline in the supine position. HRV data were analyzed by the method of coarse graining spectral analysis. Variables compared between groups included mean and standard deviation (SD(RRI)) of RR intervals (RRI), amplitudes of low- (A(LF); 0.04-0.15 Hz) and high-frequency (A(HF); >0.15 Hz) harmonic as well as aperiodic, fractal (A(FR); 1/f(beta)) spectral components, the spectral exponent beta, and the difference in these values between baseline and HUT for each subject. In the supine baseline, only mean RRI was significantly (P < 0.01) lower in CFS than in CON. During HUT, however, mean RRI (P < 0.01), SD(RRI) (P < 0.01), A(HF) (P < 0.05), and A(FR) (P < 0.01) were significantly lower in CFS than in CON. When the difference in values between baseline and HUT for each subject was examined, only the difference for A(FR) (deltaA(FR)) was significantly (P < 0.01) lower in CFS than in CON, suggesting that A(FR)is a disease-specific response of HRV to HUT. When a cut-off level was set to deltaA(FR) = -2.7 msec, the sensitivity and the specificity in differentiating CFS from controls were 90% and 72%, respectively. The data suggest that a decrease in aperiodic fractal component of HRV in response to HUT can be used to differentiate patients with CFS from CON.