Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia.

OBJECTIVE: Regulation of growth hormone (GH) receptor expression and hence tissue GH sensitivity may be important for the conflicting results found in treatment studies with recombinant growth hormone in chronic heart failure (CHF). Growth hormone-binding protein (GHBP) corresponds to the extracellular domain of the GH receptor and is closely related to measures of body composition and, specifically, to size of visceral fat tissue. Leptin, the adipocyte specific (ob) gene product, has been proposed as the signal linking adipose tissue and GHBP/GH-receptor expression. CHF has recently been shown to be a hyperleptinaemic and insulin-resistant state regardless of aetiology. This study aimed to examine the influence of leptin on GHBP in CHF patients with and without cardiac cachexia compared with healthy control subjects. METHODS: We studied 47 male patients with CHF (mean age 61+/-2 years, New York Heart Association (NYHA)-class 2.7+/-0.1, left ventricular ejection fraction (LVEF) 28+/-2%, peak oxygen consumption 16.8+/-0.9 ml/kg/min) and 21 male healthy controls of similar age. Of the CHF patients, 19 were cachectic (cCHF; non-oedematous weight loss >7.5% over at least 6 months) and 28 non-cachectic (ncCHF; similar for age and LVEF). Insulin sensitivity was assessed by an intravenous glucose tolerance test using the minimal model approach. RESULTS: Compared with healthy controls, patients had elevated levels of leptin (7.6+/-0.7 vs 4.8+/-0.7 ng/ml, P<0.05), insulin (76.2+/-8.9 vs 41.4+/-6.0 pmol/l, P<0.01), and reduced insulin sensitivity (2.43+/-0.2 vs 3.48+/-0.3 min(-1).microU.ml(-1).10(4), P<0.005) but similar GHBP levels (901+/-73 vs 903+/-95 pmol/l). Leptin levels were increased in ncCHF (9.11+/-1.0 ng/ml, P=0.001) but were not different from normal in cCHF (5.32+/-0.7 ng/ml, P>0.5). After correction for total body fat mass, both ncCHF and cCHF were hyperleptinaemic (41.8+/-3.8 and 37.9+/-0.38 vs 24.4+/-2.1 ng/ml/100 g, ANOVA P=0.001). In both patients and controls there was a direct correlation between leptin levels and GHBP (r=0.70 and r=0.71 respectively, both P<0.0001). This relationship was stronger than between GHBP and several parameters of body composition (body mass index (BMI), total and regional body fat mass or % body fat) and held true when sub-groups were tested individually (ncCHF r=0.62, P<0.001; cCHF r=0.79, P<0.0001). In multivariate regression analysis in all CHF patients, serum leptin levels emerged as the strongest predictor of GHBP, independent of age, BMI, total and regional fat mass or % body fat, fasting insulin level and insulin sensitivity. CONCLUSION: Fat mass corrected leptin levels are elevated in CHF patients with and without cachexia. Reduced total fat mass may account for lower leptin levels in cachectic CHF patients compared with non cachectic patients. Leptin strongly predicts GHBP levels in CHF regardless of its hyperleptinaemic state or severely altered body composition as in cardiac cachexia. Leptin could be the signalling link between adipose tissue and GHBP/GH receptor expression in CHF.

Wasting as an independent predictor of mortality in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is the most common life threatening autosomal recessive disorder in the white population. Wasting has long been recognised as a poor prognostic marker in CF. Whether it predicts survival independently of lung function and arterial blood gas tensions has not previously been reported. METHODS: 584 patients with CF (261 women) of mean (SD) age 21 (7) years were studied between 1985 and 1996, all of whom were being followed up in a tertiary referral centre. Lung function tests, body weight, arterial blood oxygen (PaO(2)) and carbon dioxide (PaCO(2)) tensions were measured. The weight was calculated as a percentage of the ideal body weight for age, height, and sex. RESULTS: Forced expiratory volume in one second (FEV(1)) recorded at the start of the study was 1.8 (1.0) l (52 (26)% predicted FEV(1)), PaO(2) 9.8 (1.9) kPa, PaCO(2) 5.0 (0.9) kPa, and % ideal weight 92 (18)%. During the follow up period (45 (27) months) 137 patients died (5 year survival 72%, 95% CI 67 to 73). FEV(1), % predicted FEV(1), PaO(2), % ideal weight (all p<0.0001), and PaCO(2) (p=0.04) predicted survival. In multivariate analysis, % predicted FEV(1) (p<0.0001), % ideal weight (p=0.004), and PaCO(2) (p=0.02) were independent predictors of outcome. Patients with >85% ideal body weight had a better prognosis at 5 years (cumulative survival 84%, 95% CI 79 to 89) than those with < or =85% ideal weight (survival 53%, 95% CI 45 to 62), p<0.0001. Percentage predicted FEV(1) (area under curve 0.83; 95% CI 0.78 to 0.87) and % ideal weight (area under curve 0.74; 95% CI 0.68 to 0.79) were accurate predictors of survival at 5 years follow up (receiver-operating characteristic analysis). CONCLUSIONS: Body wasting is a significant predictor of survival in patients with CF independent of lung function, arterial blood oxygen and carbon dioxide tensions.

High tumour necrosis factor-alpha levels are associated with exercise intolerance and neurohormonal activation in chronic heart failure patients.

Immune activation plays an important role in the progression of chronic heart failure (CHF). We sought to investigate whether different degrees of tumor necrosis factor-alpha (TNF-alpha) activation are associated with exercise intolerance, neurohormonal activation and alterations in muscle mass and function in patients with CHF without cardiac cachexia. Patients were divided into quartiles according to their TNF levels (first quartile: 0.98-4.90 pg/ml, second quartile: 5.00-6.60 pg/ml; third quartile 6.80-9.00 pg/ml; fourth quartile 9.80-32.00 pg/ml). Patients underwent cardiopulmonary exercise testing, quadriceps muscle strength test, quadriceps fatigue test, and assessment of thigh muscle and fat cross-sectional area (CSA) by computerized tomography scanning. Patients in the highest TNF quartile had the lowest peak oxygen consumption [13.1 (+/-4.1) ml/kg/min vs 18.1 (+/-5.3), 18.8 (+/-4.8) and 18.7 (+/-5.6) ml/kg/min, P<0.01] the greatest relation of ventilation and dioxide production (VE/VCO(2)) slope (P<0.05) and the most elevated catecholamine levels (P<0.05) compared to patients in the first three quartiles. Patients with the lowest TNF levels had preserved thigh muscle size and quadriceps strength. Strength/muscle CSA was similar in the four groups. Muscle strength during fatigue testing was significantly lower in the fourth quartile (P=0.01) compared with the other three groups. In CHF patients only the highest levels of TNF are associated with poor functional status and neurohormonal activation. This group of patients may represent the appropriate target population for TNF antagonism.

Uric acid in cachectic and noncachectic patients with chronic heart failure: relationship to leg vascular resistance.

BACKGROUND: Chronic heart failure (CHF) is a hyperuricemic state, and capillary endothelium is the predominant site of xanthine oxidase in the vasculature. Upregulated xanthine oxidase activity (through production of toxic free radicals) may contribute to impaired regulation of vascular tone in CHF. We aimed to study the relationship between serum uric acid levels and leg vascular resistance in patients with CHF with and without cachexia and in healthy control subjects. METHODS: In 23 cachectic and 44 noncachectic patients with CHF (age, 62 +/- 1 years, mean +/- SEM) and 10 healthy control subjects (age, 68 +/- 1 years), we assessed leg resting and postischemic peak vascular resistance (calculated from mean blood pressure and leg blood flow by venous occlusion plethysmography). RESULTS: Cachectic patients, compared with noncachectic patients and control subjects, had the highest uric acid levels (612 +/- 36 vs 459 +/- 18 and 346 +/- 21 micromol/L, respectively, both P <.0001) and the lowest peak leg blood flow and vascular reactivity (reduction of leg vascular resistance from resting to postischemic conditions: 83% vs 88% and 90%, both P <.005). In all patients, postischemic vascular resistance correlated significantly and independently of age with uric acid (r = 0.61), creatinine (r = 0.47, both P <.0001), peak VO2 (r = 0.34), and New York Heart Association class (r = 0.33, both P <.01). This correlation was not present in healthy control subjects (r = -0.04, P =.9). In multivariate and stepwise regression analyses, serum uric acid emerged as the strongest predictor of peak leg vascular resistance (standardized coefficient = 0.61, P <.0001) independent of age, peak VO2, creatinine, New York Heart Association class, and diuretic dose. CONCLUSIONS: Hyperuricemia and postischemic leg vascular resistance are highest in cachectic patients with CHF, and both are directly related independent of diuretic dose and kidney function. The xanthine oxidase metabolic pathway may contribute to impaired vasodilator capacity in CHF.

[Tumor necrosis factor alpha in chronic heart failure. Clinical manifestation and therapeutic possibilities]. / Tumor-Nekrose-Faktor alpha bei chronischer Herzinsuffizienz. Klinische Manifestation und therapeutische Möglichkeiten.

BACKGROUND: Chronic heart failure (CHF) may be seen as a multi-system disorder with its origin in the heart but including many extracardiac manifestations. Immunological abnormalities are recognized in this context, in particular, changes in the expression of mediators of the innate immune response. IMPORTANCE OF TNF: Higher levels of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF) are found in the circulation and in the myocardium of patients with chronic heart failure than in controls. TNF has been implicated in a number of pathophysiological processes that are thought to be important to the progression of chronic heart failure. Therapies directed against this cytokine might therefore represent a novel approach to heart failure management.

Tumour necrosis factor in chronic heart failure: a peripheral view on pathogenesis, clinical manifestations and therapeutic implications.

The development of chronic heart failure (CHF) includes phenotypic changes in a host of homeostatic systems so that, as the disease advances, CHF may be seen as a multi-system disorder with its origins in the heart but embracing many extra-cardiac manifestations. Immunological abnormalities are recognised in this context, in particular, changes in the expression of mediators of the innate immune response. Higher levels of the pro-inflammatory cytokine tumor necrosis factor (TNF) are found in the circulation and in the myocardium of patients with CHF than in controls, and TNF has been implicated in a number of pathophysiological processes that are thought important to the progression of CHF. Therapies directed against this cytokine therefore represent a novel approach to heart failure management. Anti-TNF strategies in CHF may target the mechanisms of immune activation, the intracellular pathways regulating TNF production, or the fate of TNF once it has been released into the circulation. Circulating endotoxin may be an important stimulus to TNF production by circulating monocytes, tissue macrophages and cardiac myocytes in CHF and efforts to limit this phenomenon are of interest. Several established pharmacological therapies for patients with CHF, including angiotensin converting enyzme inhibitors, beta-blockers, and phosphodiesterase inhibitors may modify cellular TNF production by their action on intracellular mechanisms, whereas TNF receptor fusion proteins have been developed that target circulating TNF itself. Patients with New York Heart Association class IV symptoms, those with cardiac cachexia and those with oedematous decompensation of their disease have the highest serum TNF levels and are most likely to benefit most from such a therapeutic approach.