Inflammation and perturbation of the l-carnitine system in heart failure

BACKGROUND: Heart failure (HF) is accompanied by elevated levels of pro-inflammatory cytokines. Skeletal muscle myopathy with atrophy of fibres, decreased oxidative metabolism and preferential synthesis of fast myosin heavy chains (MHCs) occurs, which contributes to the worsening of symptoms. l-Carnitine has been shown to be protective against the apoptosis-induced atrophy of fibres and fast MHCs shift. AIMS: To investigate the interrelationship between TNFalpha and sphingosine (SPH), which induce muscle wastage, and plasma levels of l-carnitine. METHODS: We studied 18 heart failure patients and correlated NYHA class and ventricular function with the plasma concentration of these molecules. RESULTS: TNFalpha and SPH levels were raised and correlated with the severity of HF. l-Carnitine levels were increased in HF patients, but decreased according to the severity of cardiac decompensation. CONCLUSIONS: The increased levels of l-carnitine are likely due to release from the damaged muscle, reduced urinary excretion, decreased dietary intake and liver synthesis (malnutrition). It is possible that the cytokine-induced muscle wastage is not counterbalanced by the beneficial metabolic effects of l-carnitine, the metabolism of which is profoundly perturbed in CHF. l-Carnitine supplementation may produce positive effects on the skeletal muscle, as has been shown in animal models of HF.     

Preclinical and clinical assessment of the safety and potential efficacy of thalidomide in heart failure

BACKGROUND: Inflammatory mediators, especially tumor necrosis factor (TNF), have been implicated in heart failure (HF). Thalidomide has anti-inflammatory properties and selectively inhibits TNF. Thus far, thalidomide or thalidomide analogues have not been evaluated in patients with heart failure. METHODS: Thalidomide was assessed in preclinical and clinical studies. First, isolated cardiac myocytes were pretreated with thalidomide or thalidomide analogues, and TNF production was assessed after lipopolysaccharide (LPS) provocation. Second, to determine the safety and potential efficacy of thalidomide, an open-label dose escalation safety study was conducted in seven patients with advanced heart failure. RESULTS: Thalidomide and thalidomide analogues inhibited LPS-induced TNF biosynthesis in cardiac myocytes in a dose-dependent manner. Thalidomide analogues had a greater inhibitory effect on TNF production than did thalidomide. In patients with advanced HF, thalidomide was safe and potentially effective when used at lower doses. However, dose-limiting toxicity was observed in two patients. There was a significant increase in the 6-minute walk distance and a trend toward improvement in left ventricular ejection fraction and quality of life after 12 weeks of maintenance therapy with thalidomide. CONCLUSIONS: Taken together these results suggest that thalidomide or its derivatives may be useful in selected patients with HF. This potential needs to be studied in larger clinical trials.     

Thalidomide salvages lethal hepatic necroinflammation and accelerates recovery from cirrhosis in rats

BACKGROUND/AIMS: The authors investigated the feasibility of thalidomide employed to treat liver fibrosis. METHODS: A cirrhotic model was established using Sprague-Dawley rats fed thioacetamide. Thalidomide-treated group was given thalidomide (10mg/kg/day) intraperitoneally for 10 consecutive days. Mortality, histopathological changes, TNFalpha, TGFbeta1, TIMP-1 and TIMP-2 were determined. Expression of TNFalpha and TGFbeta1 mRNA of Kupffer's cells derived from the experimental rats were determined. RESULTS: The mortality rates of thalidomide-treated group and vehicle-treated group were 8 and 32%, respectively. The total Knodell score of thalidomide-treated rats was lower than those of vehicle-treated rats. Micro-nodular cirrhosis resolved grossly in thalidomide-treated rats on day 28; while vehicle-treated rats continued to display uneven liver surface on day 28. Expression of TNFalpha, TGFbeta1, TIMP-1, and TIMP-2 was decreased in thalidomide-treated rats compared to those treated with vehicles. Finally, the expression of TNFalpha and TGFbeta1 mRNA of Kupffer's cells derived from rats treated with thalidomide were much lower than those treated with vehicle. CONCLUSIONS: Thalidomide salvages lethal hepatic necroinflammation, accelerates recovery from cirrhosis in rats, and works by suppressing of TNFalpha and TGFbeta1 production of Kupffer's cells.     

Exercise training in chronic heart failure: effects on pro-inflammatory markers

BACKGROUND: Acute bouts of exercise have been shown to induce inflammatory cytokine activation and peripheral hypoxia in patients with chronic heart failure (CHF). In this study, we set out to investigate the impact of chronic exercise training on pro-inflammatory cytokines and markers of endothelial damage. METHODS AND RESULTS: We measured tumor necrosis factor alpha (TNFalpha), its soluble TNF-receptors 1 and 2, interleukin 6 (IL-6), soluble e-selectin, soluble intracellular adhesion molecule-1 (sICAM) and sCD14 in 18 patients with CHF and 9 age-matched controls in a randomized cross-over study of 8 weeks of exercise training (5 days/week, submaximal bicycle ergometer training, 30 min/day; calisthenics 9 min/day) versus 8 weeks of rest. At baseline, patients had a lower peak Vo(2) (p=0.009) and a trend for higher levels of e-selectin (p=0.08) and sCD14 (p=0.06), in addition to significantly elevated levels of sICAM (p=0.02), TNFalpha (p=0.02) and TNF-R2 (p=0.002); TNF-R1 and IL-6 were not elevated. Although exercise training was effective and led to an increase in peak Vo(2) in CHF (p<0.003), there was no activation of any of the above variables observed, neither in patients nor controls. CONCLUSIONS: Chronic heart failure is associated with increased levels of TNFalpha and markers of endothelial damage. Whereas acute bouts of exercise have been reported to lead to an increase in pro-inflammatory cytokines and markers of endothelial damage, these effects are not seen when exercise is performed chronically.     

Thalidomide attenuates the development of fibrosis during post-infarction myocardial remodelling in rats

BACKGROUND: Inflammation plays a pathogenic role in the development of heart failure (HF). The aim of this study was to examine the effect of treatment with the immunomodulating drug thalidomide in a rat model for post-myocardial infarction (MI) HF. METHODS: Rats were subjected to MI by left coronary artery ligation or sham-operated. Seven days after surgical intervention rats were randomised to treatment with thalidomide or vehicle for 8 weeks. RESULTS: Our main findings were: (i) thalidomide treatment did not affect cardiac function or the hypertrophic response, as determined by haemodynamic measurements and heart chamber weights, respectively. (ii) HF rats treated with thalidomide had a minor reduction in septum and relative wall thickness (p<0.05), indicating an anti-remodelling effect. (iii) Thalidomide appeared to have immunostimulatory effects on the myocardium as evident by increased MIP-1alpha gene expression (p<0.05). (iv) Treating HF rats with thalidomide reduced myocardial collagen content, as assessed by markedly decreased levels of hydroxyproline ( approximately 40% reduction; p<0.05), accompanied by lower TGF-beta(1) gene expression (p<0.05). CONCLUSION: Although thalidomide had no effect on cardiac function, our results suggest that intervention with thalidomide may have beneficial effects in post-MI HF by attenuating collagen accumulation and development of myocardial fibrosis.     

Specific changes in skeletal muscle myosin heavy chain composition in cardiac failure: differences compared with disuse atrophy as assessed on microbiopsies by high resolution electrophoresis.

OBJECTIVE: In congestive heart failure (CHF) the skeletal muscle of the lower limbs develops a myopathy with atrophy and shift from the slow type to the fast type fibres. The aim was to test the hypothesis that this myopathy is specific and not simply related to detraining, by comparing patients with different degrees of CHF with patients with severe muscle atrophy due to disuse. DESIGN: Case-control study involving 50-150 micrograms needle biopsies of the gastrocnemius muscle. By an electrophoretic micromethod, the three isoforms of myosin heavy chains (MHC) were separated. PATIENTS: Five patients restricted to bed for more than one year because of stroke with disuse atrophy and normal ventricular function, and 19 with CHF were studied. There were seven age matched controls. MAIN OUTCOME MEASURES: The percentage of MHC1 (slow isoform), MHC2a (fast oxidative), and MHC2b (fast glycolytic) was determined by densitometric scan and correlated with indices of severity of cardiac failure. RESULTS: Ejection fraction was 42.5 (SD 15.2)% in CHF, 59.5 (1.0)% in disuse atrophy and 60.3 (1.4)% in controls (P < 0.001 v both). The degree of muscle atrophy as calculated by the body mass index/gastrocnemius cross sectional area, showed a profound degree of atrophy in patients with muscle disuse [0.94 (0.39)]. This was worse than in the controls [4.27 (0.16), P < 0.0005] and the CHF patients [2.60 (1.10), P < 0.005]. Atrophy in CHF patients was also greater than in controls (P < 0.005). MHC1 was lower in CHF than in disuse atrophy [51.83 (15.04) v 84.5 (17.04), P < 0.01] while MHC2b was higher [23.5 (7.4) v 7.25 (7.92), P < 0.001]. There was a similar trend for MHC2a [24.83 (15.01) v 8.25 (9.12), P < 0.05]. Within the CHF group there was a positive correlation between NYHA class and MHC2a (r = 0.47, P < 0.05) and MHC2b (r = 0.55, P < 0.01) and a negative correlation between NYHA class and MHC1 (r = -0.74, P < 0.001). Similarly, significant correlations were found for ejection fraction, diuretic consumption score, exercise test tolerance, and degree of muscle atrophy. CONCLUSIONS: The CHF myopathy appears to be specific and not related to detraining. The magnitude of MCH redistribution correlates with the severity of the disease. The electrophoretic micromethod used is very sensitive and reproducible. Biopsies are so well tolerated that can be repeated frequently, allowing thorough follow up.     

Apoptosis in the skeletal muscle of rats with heart failure is associated with increased serum levels of TNF-alpha and sphingosine

Skeletal muscle in congestive heart failure (CHF) is responsible for increased fatigability, decreased endurance and exercise capacity. A specific myopathy with increased expression of fast myosin heavy chains (MHCs), myocyte atrophy, secondary to myocyte apoptosis, that is triggered by high levels of circulating tumor necrosis factor (TNF-alpha) has been described. However, a direct effect of TNF-alpha on skeletal muscle has not been described yet. In this paper we put forward the hypothesis that TNF-alpha plays an indirect effect on skeletal myocytes. In an animal model of CHF, the monocrotaline-treated rat, we have observed a significant (P<0.001) increase of circulating TNF-alpha that is paralleled by increased serum levels of the endogenous second messenger, sphingosine (SPH), (from 0.71+/-0.15 to 1.32+/-0.39 nmoles/ml, P<0.01). In the tibialis anterior (TA) muscle we found a marked increase of myocyte apoptosis (from 1.4+/-2.4 to 40.1+/-39.5 nuclei/mm(3), P<0.04). We correlated plasma levels of TNF-alpha with those of SPH and in turn with the magnitude of apoptosis. Linear regression showed a significant correlation between TNF-alpha, SPH, and apoptosis (r(2)=0.74, P=0.004 and r(2)=0.87, P=0.001 respectively). Analysis of covariance showed that TNF-alpha and SPH were independently correlated with the number of apoptotic nuclei (P=0.0001). In parallel in vitro experiments, where increasing concentrations of SPH were applied to skeletal muscle cells in culture, we observed a dose-dependent increase in apoptosis. These results suggest that TNF-alpha-induced SPH production may be responsible for skeletal muscle apoptosis. The link between TNF-alpha and skeletal muscle apoptosis could be represented by the second messenger SPH, which can directly induce apoptosis in these cells.     

Thalidomide ameliorates carbon tetrachloride induced cirrhosis in the rat

OBJECTIVE: Thalidomide has anti-inflammatory, anti-tumour necrosis factor-alpha and anti-collagen activities. Cirrhosis is characterized by inflammation and fibrosis. Thus, thalidomide was evaluated in an experimental model of liver cirrhosis. METHODS: Male Wistar rats were used. Group 1 (n = 8) received mineral oil i.p. (control); group 2 (n = 15) received CCl(4) i.p. for 8 weeks to induce cirrhosis; group 3 (n = 15) consisted of rats receiving CCl(4) plus thalidomide (200 mg/kg/12 h); animals in group 4 (n = 8) received thalidomide only. Alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gamma-GTP) and alkaline phosphatase (ALP) were measured in serum, while collagen (hydroxyproline), glycogen and lipid peroxidation were determined in liver samples. A liver histopathological analysis was performed by using Gomori's trichromic staining. RESULTS: Intoxication with CCl(4) induced 33.3% mortality, while thalidomide co-treatment reduced it to 13.3%. The serum activities of ALT, gamma-GTP and ALP increased 3, 2 and 4-fold by CCl(4) treatment; thalidomide completely prevented elevation of these enzymes. In the liver, lipid peroxidation increased about 20-fold and glycogen was abolished in CCl(4) cirrhotic rats; thalidomide completely prevented the former and partially (P < 0.05) the latter. CCl(4) treated rats revealed a loss of normal architecture and nodules of hepatocytes surrounded by thick bands of collagen. Thalidomide + CCl(4) treated rats showed minor histological alterations and thinner bands of collagen. The anti-fibrotic effect estimated by hydroxyproline was partial but significant (P < 0.05). CONCLUSION: Thalidomide prevented necrosis, cholestasis and fibrosis induced by CCl(4). Its mechanism of action may be related to its anti-inflammatory, anti-tumour necrosis factor-alpha and anti-fibrotic activities reported previously.     

Thalidomide in treatment of connective diseases and vasculities

Thalidomide is an immunomodulatory, anti-inflammatory and anti-angiogenic drug. Thalidomide exerts its effects by decreasing circulating CD4 positive T-cells and stimulating CD8 positive T-cells, by increasing the number of Natural Killer cells and T-helper 2 cells. Thalidomide also inhibits proliferation of stimulated T-cells and leukocyte chemotaxis. It modifies a number of integrin receptors and other leukocytic surface receptors and down-modulates cell-adhesion molecules involved in leukocyte migration. It has been demonstrated that thalidomide inhibits TNFalpha, IL-5, IL-6, IL-8, IL-12 production and increases production of IL-2, IL-10 and INFgamma. Moreover thalidomide plays an important role in inhibition of VEGF and FGF-2 mediated angiogenesis. Although the exact mechanism of action is not fully understood and only limited treatment opinions exist, thalidomide plays a role also in connective diseases and vasculities. Thalidomide has been seen efficacious in the treatment of cutaneous disorders in patients with systemic lupus erythematosus and in mucocutaneous disease in Behcet's disease with a not dose-dependent response, even if it should be restricted to selected patients because of its important side effects.     

Cardiac and skeletal muscle energy metabolism in heart failure: beneficial effects of voluntary activity

OBJECTIVE: Mitochondrial function and metabolic profile of slow and fast skeletal muscles and cardiac muscle are altered in chronic heart failure (CHF), suggesting a generalized metabolic myopathy in this disease. The aim of this study was to investigate the potential beneficial effects of voluntary activity on cardiac and skeletal muscle energetics in heart failure. METHODS: Heart failure was induced in rats by aortic stenosis. Four months after surgery, part of sham and CHF animals were randomly assigned to activity cages equipped with running wheels for 8 weeks or kept sedentary. Mitochondrial capacity and regulation were measured using saponin skinned fibers in left ventricle, slow and fast skeletal muscles, and metabolic and myosin profiles were established. RESULTS: Despite four times lower performances of CHF rats, alterations in metabolic and myosin parameters (oxidative capacity, mitochondrial enzymes, cytosolic and mitochondrial creatine kinase, myosin heavy chains) observed in all muscles of CHF animals were almost fully restored in soleus muscle though unchanged in heart and fast skeletal muscles. CONCLUSIONS: These results show the powerful beneficial effect of physical activity specifically on active slow oxidative skeletal muscle in CHF, without the worsening of cardiac muscle metabolism.     

Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial

BACKGROUND: Proinflammatory cytokines, especially tumour necrosis factor alpha (TNF-alpha), play a prominent role in the pathogenesis of cancer cachexia. Thalidomide, which is an inhibitor of TNF-alpha synthesis, may represent a novel and rational approach to the treatment of cancer cachexia. AIMS: To assess the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia secondary to advanced pancreatic cancer. METHODS: Fifty patients with advanced pancreatic cancer who had lost at least 10% of their body weight were randomised to receive thalidomide 200 mg daily or placebo for 24 weeks in a single centre, double blind, randomised controlled trial. The primary outcome was change in weight and nutritional status. RESULTS: Thirty three patients (16 control, 17 thalidomide) were evaluated at four weeks, and 20 patients (eight control, 12 thalidomide) at eight weeks. At four weeks, patients who received thalidomide had gained on average 0.37 kg in weight and 1.0 cm(3) in arm muscle mass (AMA) compared with a loss of 2.21 kg (absolute difference -2.59 kg (95% confidence interval (CI) -4.3 to -0.8); p = 0.005) and 4.46 cm(3) (absolute difference -5.6 cm(3) (95% CI -8.9 to -2.2); p = 0.002) in the placebo group. At eight weeks, patients in the thalidomide group had lost 0.06 kg in weight and 0.5 cm(3) in AMA compared with a loss of 3.62 kg (absolute difference -3.57 kg (95% CI -6.8 to -0.3); p = 0.034) and 8.4 cm(3) (absolute difference -7.9 cm(3) (95% CI -14.0 to -1.8); p = 0.014) in the placebo group. Improvement in physical functioning correlated positively with weight gain (r = 0.56, p = 0.001). CONCLUSION: Thalidomide was well tolerated and effective at attenuating loss of weight and lean body mass in patients with cachexia due to advanced pancreatic cancer.     

Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow

We and others have previously demonstrated excessive phosphocreatine (PCr) depletion and acidosis in skeletal muscle during exercise in patients with congestive heart failure (CHF). In the present study, we performed serial measurements of PCr and pH during gradually incremental flexor digitorum superficialis exercise in 22 patients with CHF and 11 age-matched controls to determine: (1) whether abnormalities were present at the same relative workloads (a comparison that would at least partially compensate for differences in muscle mass), (2) the temporable course of the metabolic changes, (3) the relationship of the metabolic findings to clinical variables, and (4) the relationship of the metabolic abnormalities to forearm blood flow. The patients with CHF had significantly lower [PCr] and pH at all submaximal levels of exercise, and these abnormalities were apparent from the onset of low-level exercise. There was considerable heterogeneity among the patients with CHF with respect to the metabolic findings, with 14 of 22 exhibiting either PCr or pH values more than 2 SDs below normal. Patients whose capacity was more limited during the protocol had lower [PCr], and especially pH, at low loads than did other patients with CHF or the control subjects. The more symptomatic patients and those with more limited bicycle exercise tolerance also had lower pH values. In contrast, there were no significant differences in forearm blood flow between the patients and controls and no relationship between forearm blood and either clinical variables or the metabolic findings. These results indicate that skeletal muscle metabolic abnormalities are present in many patients with CHF and that they are not primarily due to either muscle atrophy or impaired blood flow. These changes may explain in part the marked heterogeneity of symptom status and exercise capacity of patients with similar degrees of cardiac dysfunction.     

Oxidative capacity of skeletal muscle in heart failure patients versus sedentary or active control subjects

OBJECTIVES: We investigated the in situ properties of muscle mitochondria using the skinned fiber technique in patients with chronic heart failure (CHF) and sedentary (SED) and more active (ACT) controls to determine: 1) whether respiration of muscle tissue in the SED and ACT groups correlates with peak oxygen consumption (pVO(2)), 2) whether it is altered in CHF, and 3) whether this results from deconditioning or CHF-specific myopathy.BACKGROUND: Skeletal muscle oxidative capacity is thought to partly determine the exercise capacity in humans and its decrease to participate in exercise limitation in CHF.METHODS: M. Vastus lateralis biopsies were obtained from 11 SED group members, 10 ACT group members and 15 patients with CHF at the time of transplantation, saponine-skinned and placed in an oxygraphic chamber to measure basal and maximal adenosine diphosphate (ADP)-stimulated (V(max)) respiration rates and to assess mitochondrial regulation by ADP. All patients received angiotensin-converting enzyme (ACE) inhibitors.RESULTS: The pVO(2) differed in the order CHF < SED < ACT. Compared with SED, muscle alterations in CHF appeared as decreased citrate synthase, creatine kinase and lactate dehydrogenase, whereas the myosin heavy chain profile remained unchanged. However, muscle oxidative capacity (V(max), CHF: 3.53 +/- 0.38; SED: 3.17 +/- 0.48; ACT: 7.47 +/- 0.73, micromol O(2).min(-1).g(-1)dw, p < 0.001 vs. CHF and SED) and regulation were identical in patients in the CHF and SED groups, differing in the ACT group only. In patients with CHF, the correlation between pVO(2) and muscle oxidative capacity observed in controls was displaced toward lower pVO(2) values.CONCLUSIONS: In these patients, the disease-specific muscle metabolic impairments derive mostly from extramitochondrial mechanisms that disrupt the normal symmorphosis relations. The possible roles of ACE inhibitors and level of activity are discussed.     

Reduction of insulin-like growth factor-I expression in the skeletal muscle of noncachectic patients with chronic heart failure

OBJECTIVES: We sought to assess the role of insulin-like growth factor-I (IGF-I) in muscle wasting in chronic heart failure (CHF), serum concentrations and local muscular IGF-I expression were determined in patients with severe CHF. BACKGROUND: Chronic heart failure is associated with progressive muscle atrophy, leading to cardiac cachexia. Skeletal muscle disuse and inflammatory activation with elevated cytokine levels have been implicated; however, the pathomechanism involved remains largely unknown. METHODS: Serum levels of IGF-I were measured by competitive solid phase immunoassay in 47 patients with severe CHF (left ventricular ejection fraction < or =30%) and 15 age-matched healthy subjects (HS). Insulin-like growth factor-I and IGF-I receptor expression were assessed in vastus lateralis biopsies by real-time PCR and Western blot analysis. RESULTS: Although serum IGF-I was not significantly different (175 +/- 10 ng/ml in CHF vs. 170 +/- 12 ng/ml in HS, p = NS), local muscle IGF-I mRNA expression was reduced by 52% in CHF (6.7 +/- 0.4 vs. 14.0 +/- 0.9 arbitrary units in HS, p < 0.001). This was accompanied by an increase in IGF-I receptor mRNA expression (86.8 +/- 5.4 in CHF vs. 23.1 +/- 1.8 arbitrary units in HS, p < 0.001). Local IGF-I expression was significantly correlated with muscle cross-sectional area (R = 0.75, p = 0.01). Chronic heart failure patients with a body mass index of < 25 kg/m(2) showed signs of peripheral growth hormone (GH) resistance, as indicated by elevated serum GH, and reduced IGF-I levels. CONCLUSIONS: In CHF patients, muscle IGF-I expression is considerably reduced in the presence of normal serum IGF-I levels, possibly contributing to early loss of muscle mass. These findings are consistent with a potential role of IGF-I for skeletal muscle atrophy in CHF.     

Thalidomide and tuberculosis.

The anti-inflammatory and immunomodulatory effects of thalidomide have led scientists to explore its clinical therapeutic values. Thalidomide is now being considered as an adjuvant treatment for tuberculosis. This literature review examines the drug's mechanism of action and clinical applications. Thalidomide affects cytokine production and T lymphocyte proliferation. It appears that thalidomide suppresses TNF-alpha production by macrophages and thereby reduces inflammatory response. Thalidomide elevates the IFN-gamma level and modulates several other cytokines as well, noteworthily IL-2 and IL-12. Thalidomide costimulates T lymphocytes, with greater effect on CD8+ than on CD4+ T cells. This finding is important, since CD8+ T cells have been shown to be contributory to the protective immune response to Mycobacterium tuberculosis infection. The clinical application of thalidomide as part of standard tuberculosis therapy is inconclusive amid variability among reports. However, thalidomide has been shown to be an effective adjuvant for tuberculosis patients complicated with severe inflammatory reaction or wasting conditions.     

Cancer cachexia

OBJECTIVES: Chronic heart failure (CHF) has emerged as an insulin-resistant state, independently of ischaemic aetiology. The underlying mechanisms of this finding are not known. Catecholamines, tumor necrosis factor alpha (TNFalpha) and leptin, the adipocyte specific hormone, have all been implicated as mediators of impaired insulin sensitivity. The purpose of this study was to examine in patients with CHF and in comparison to healthy controls subjects whether norepinephrine, TNFalpha or leptin relate to insulin sensitivity. DESIGN: 41 patients with CHF (age 60+/-2 years, NYHA I/II/III/IV 4/12/22/3, peak oxygen consumption 17.6+/-1.0 ml/kg per min) and 21 healthy controls of similar age and total and regional fat distribution were studied in a cross-sectional study. Insulin sensitivity was assessed by intravenous glucose tolerance testing using the minimal model approach; catecholamines, TNFalpha and soluble TNF receptors 1 and 2 were also measured. Total and regional body fat mass was assessed by dual energy X-ray absorptiometry. RESULTS: Insulin sensitivity was reduced in CHF patients compared to controls by 31% (P<0.01) and fasting insulin was higher in patients than in controls (79.1+/-9.7 vs. 41.4+/-6.0 pmol/l, P<0.01). Patients had, compared to healthy controls, elevated serum leptin levels (8.28+/-0.84 vs. 4.83+/-0.68 ng/ml), norepinephrine (3.45+/-0.34 vs. 1.87+/-0.16 nmol/l, both P<0.01) and soluble TNF-receptors 1 (1280+/-141 vs. 639+/-52 pg/ml) and 2 (2605+/-184 vs. 1758+/-221 pg/ml, both P<0.01). Leptin levels corrected for total body fat mass were higher in CHF patients than in controls (41.3+/-3 vs. 24.3+/-2 pg/ml per 100 g, P<0.001). TNFalpha was not significantly different between the groups. In both groups there was an inverse correlation between insulin sensitivity and serum leptin (r=-0.65, P<0.0001 for pooled subjects); in contrast, no significant relation was found between insulin sensitivity and norepinephrine or TNFalpha. In multivariate regression analysis, leptin emerged as the only significant predictor of insulin sensitivity (standardised coefficient=-0.59, P<0.001), independent of body fat mass, age and peak VO2. CONCLUSION: In moderate CHF, elevated leptin levels directly and independently predict insulin resistance. Elevated serum leptin levels could play a role in the impaired regulation of energy metabolism in CHF. In contrast to observations in other conditions, TNFalpha and norepinephrine are not related to insulin resistance in moderate CHF.     

Thalidomide-induced acute cholestatic hepatitis: Case report and review of the literature

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.     

Reduced exercise tolerance in CHF may be related to factors other than impaired skeletal muscle oxidative capacity

BACKGROUND: We sought to determine whether skeletal muscle oxidative capacity, fiber type proportions, and fiber size, capillary density or muscle mass might explain the impaired exercise tolerance in chronic heart failure (CHF). Previous studies are equivocal regarding the maladaptations that occur in the skeletal muscle of patients with CHF and their role in the observed exercise intolerance.Methods and results Total body O(2) uptake (VO(2peak)) was determined in 14 CHF patients and 8 healthy sedentary similar-age controls. Muscle samples were analyzed for mitochondrial adenosine triphosphate (ATP) production rate (MAPR), oxidative and glycolytic enzyme activity, fiber size and type, and capillary density. CHF patients demonstrated a lower VO(2peak) (15.1+/-1.1 versus 28.1+/-2.3 mL.kg(-1).min(-1), P<.001) and capillary to fiber ratio (1.09+/-0.05 versus 1.40+/-0.04; P<.001) when compared with controls. However, there was no difference in capillary density (capillaries per square millimeter) across any of the fiber types. Measurements of MAPR and oxidative enzyme activity suggested no difference in muscle oxidative capacity between the groups. CONCLUSIONS: Neither reductions in muscle oxidative capacity nor capillary density appear to be the cause of exercise limitation in this cohort of patients. Therefore, we hypothesize that the low VO(2peak) observed in CHF patients may be the result of fiber atrophy and possibly impaired activation of oxidative phosphorylation.     

Contributors to cognitive impairment in congestive heart failure: a pilot case–control study

Background:  Cognitive impairment and heart failure are both serious health problems related to population ageing. Impaired cognitive function is an important but underrecognized complication of congestive heart failure (CHF). The aim of the study was to examine the sociodemographic, clinical, neuroimaging and biochemical parameters affecting cognition in CHF.
Methods:  Thirty-one patients with CHF (left-ventricular ejection fraction < 40%) and 24 controls without CHF, all free of clinically significant cognitive impairment, participating in a case–control study were assessed using a cognitive battery (CAMCOG), a depression scale, 6-min-walk test, left-ventricular ejection fraction, semi-quantitative magnetic resonance imaging, and cortisol, aldosterone and renin concentrations.
Results:  The CHF patients had lower CAMCOG scores than controls (93.5 ± 6.1 vs 99.9 ± 2.4, P < 0.001) and had significantly lower scores on visuospatial, executive function, visual memory and verbal learning tasks. Concentrations of renin and aldosterone were higher in patients with CHF (5.4 ± 6.0 vs 0.8 ± 0.7 mU/L, P < 0.001 and 598.2 ± 306.2 vs 346.0 ± 201.5, P = 0.003). Right medial temporal lobe atrophy was more prominent in CHF ( P = 0.030). Left medial temporal lobe atrophy and deep white matter hyperintensities showed moderate association with cognitive scores in CHF, whereas functional capacity and biochemical parameters were fairly correlated to cognition.
Conclusion:  Congestive heart failure is associated with a pattern of generalized cognitive decline. Structural brain changes, functional capacity and biochemical parameters are associated with the cognitive performance of patients with CHF, but their contribution appears modest. The design of a definitive case–control study is described.     

Thalidomide: an emerging drug in oral mucosal lesions

Thalidomide has reemerged as a potential drug with new found uses despite its history of having caused devastating congenital birth defects. The drug has become the subject of major interest because of its clinical value in certain clearly defined disorders. Interest in thalidomide was initially rekindled in the mid-1960s by its remarkable effect in lessening the complication of leprosy called erythema nodosum leprosum. Several studies thereafter have demonstrated the use of thalidomide as a wonder drug. However, it was only in July 1998 that the US Food and Drug Administration granted approval for the use of thalidomide under strict patient guidelines. Its apparent immunomodulatory and anti-inflammatory properties led to widespread application in clinical practice. Thalidomide has gained respectability as a promising new drug in oral mucosal lesions. Studies have suggested that thalidomide is effective in severe aphthous stomatitis, Behçet’s syndrome, certain oral manifestations of human immunodeficiency virus (HIV) infection, erosive lichen planus, and possibly malignancies.