Mathias Rauchhaus

Endotoxin and immune activation in chronic heart failure: a prospective cohort study.

BACKGROUND Immune activation in patients with chronic heart failure may be secondary to endotoxin (lipopolysaccharide) action. We investigated the hypothesis that altered gut permeability with bacterial translocation and endotoxaemia would be increased in patients with oedema secondary to congestive heart failure. METHODS We compared 20 patients who had chronic heart failure with recent-onset peripheral oedema (mean age 64 years [SD 10], New York Heart Association [NYHA] class 3.3 [0.7]), 20 stable non-oedematous patients with chronic heart failure (mean age 63 years [19], NYHA class 2.6 [0.7]), and 14 healthy volunteers (mean age 55 years [16]). Biochemical markers of endotoxaemia, inflammation, and immune activation were measured. Ten patients were studied within 1 week of complete resolution of oedema. Five patients survived longer than 6 months and were restudied again after remaining free of oedema for more than 3 months. FINDINGS Mean endotoxin concentrations were higher in oedematous patients with chronic heart failure than in stable patients with chronic heart failure (0.74 [SD 0.45] vs 0.37 EU/mL [0.23], p=0.0009) and controls (0.46 EU/mL [0.21], p=0.02). Oedematous patients had the highest concentrations of several cytokines. After short-term diuretic treatment, endotoxin concentrations decreased from 0.84 EU/mL [0.49] to 0.45 EU/mL [0.21], p<0.05) but cytokines remained raised. After freedom of oedema for more than 3 months after oedema resolved, endotoxin concentrations remained unchanged from the previous visit (0.49 EU/mL [0.06], p=0.45). INTERPRETATION Raised concentrations of endotoxin and cytokines are found in patients with chronic heart failure during acute oedematous exacerbation. Intensified diuretic treatment can normalise endotoxin concentrations. Our preliminary findings suggest that endotoxin may trigger immune activation in patients with chronic heart failure during oedematous episodes.

The endotoxin-lipoprotein hypothesis

The advent of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) has revolutionised the treatment of hypercholesterolaemia. Statin treatment, by lowering the atherogenic lipoprotein profile, reduces morbidity and mortality in patients with cardiovascular disease. Treatment with simvastatin causes a reduction of events of new-onset heart failure, but this may be attributable to properties other than its lipid-lowering effects. There is some evidence that lower serum cholesterol concentrations (as a surrogate for the totality of lipoproteins) relate to impaired survival in patients with chronic heart failure (CHF). Inflammation is a feature in patients with CHF and increased lipopolysaccharide may contribute substantially. We postulate that higher concentrations of total cholesterol are beneficial in these patients. This is potentially attributable to the property of lipoproteins to bind lipopolysaccharide, thereby preventing its detrimental effects. We hypothesise there is an optimum lipoprotein concentration below which lipid reduction would, on balance, be detrimental. We also propose that, in patients with CHF, a non-lipid-lowering statin (with ancillary properties such as immune modulatory and anti-inflammatory actions) could be as effective or even more beneficial than a lipid-lowering statin.

Uric Acid and Survival in Chronic Heart Failure Validation and Application in Metabolic, Functional, and Hemodynamic Staging

Background—Serum uric acid (UA) could be a valid prognostic marker and useful for metabolic, hemodynamic, and functional (MFH) staging in chronic heart failure (CHF). Methods and Results—For the derivation study, 112 patients with CHF (age 59±12 years, peak oxygen consumption [&OV0312;o2] 17±7 mL/kg per minute) were recruited. In separate studies, we validated the prognostic value of UA (n=182) and investigated the relationship between MFH score and the decision to list patients for heart transplantation (n=120). In the derivation study, the best mortality predicting UA cutoff (at 12 months) was 565 &mgr;mol/L (9.50 mg/dL) (independently of age, peak &OV0312;o2, left ventricular ejection fraction, diuretic dose, sodium, creatinine, and urea;P <0.0001). In the validation study, UA ≥565 &mgr;mol/L predicted mortality (hazard ratio, 7.14;P <0.0001). In 16 patients (from both studies) with UA ≥565 &mgr;mol/L, left ventricular ejection fraction ≤25% and peak &OV0312;o2 ≤14 mL/kg per min (MFH score 3), 12-month survival was lowest (31%) compared with patients with 2 (64%), 1 (77%), or no (98%, P <0.0001) risk factor. In an independent study, 51% of patients with MFH score 2 and 81% of patients with MFH score 3 were listed for transplantation. The positive predictive value of not being listed for heart transplantation with an MFH score of 0 or 1 was 100%. Conclusions—High serum UA levels are a strong, independent marker of impaired prognosis in patients with moderate to severe CHF. The relationship between serum UA and survival in CHF is graded. MFH staging of patients with CHF is feasible.

Effects of Xanthine Oxidase Inhibition With Allopurinol on Endothelial Function and Peripheral Blood Flow in Hyperuricemic Patients With Chronic Heart Failure: Results From 2 Placebo-Controlled Studies

Background—In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)–derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies. Methods and Results—In 10 CHF patients with normal serum uric acid (UA) levels (315±42 &mgr;mol/L) and 9 patients with elevated UA (535±54 &mgr;mol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 &mgr;g/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (P <0.05). In a double-blind, crossover design, hyperuricemic CHF patients were randomly allocated to allopurinol 300 mg/d or placebo for 1 week. In 14 patients (UA 558±21 &mgr;mol/L, range 455 to 743 &mgr;mol/L), treatment reduced UA by >120 &mgr;mol/L in all patients (mean reduction 217±15 &mgr;mol/L, P <0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (+24%, P =0.027) and legs (+23%, P =0.029). Flow-dependent flow improved by 58% in arms (P =0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (P <0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (r =0.63, P <0.05). Conclusions—In hyperuricemic CHF patients, XO inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically.

Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology

The reductions in mortality and morbidity being achieved among cancer patients with current therapies represent a major achievement. However, given their mechanisms of action, many anti‐cancer agents may have significant potential for cardiovascular side effects, including the induction of heart failure. The magnitude of this problem remains unclear and is not readily apparent from current clinical trials of emerging targeted agents, which generally under‐represent older patients and those with significant co‐morbidities. The risk of adverse events may also increase when novel agents, which frequently modulate survival pathways, are used in combination with each other or with other conventional cytotoxic chemotherapeutics. The extent to which survival and growth pathways in the tumour cell (which we seek to inhibit) coincide with those in cardiovascular cells (which we seek to preserve) is an open question but one that will become ever more important with the development of new cancer therapies that target intracellular signalling pathways. It remains unclear whether potential cardiovascular problems can be predicted from analyses of such basic signalling mechanisms and what pre‐clinical evaluation should be undertaken. The screening of patients, optimization of therapeutic schemes, monitoring of cardiovascular function during treatment, and the management of cardiovascular side effects are likely to become increasingly important in cancer patients. This paper summarizes the deliberations of a cross‐disciplinary workshop organized by the Heart Failure Association of the European Society of Cardiology (held in Brussels in May 2009), which brought together clinicians working in cardiology and oncology and those involved in basic, translational, and pharmaceutical science.

EURObservational Research Programme: regional differences and 1‐year follow‐up results of the Heart Failure Pilot Survey (ESC‐HF Pilot)

The ESC‐HF Pilot survey was aimed to describe clinical epidemiology and 1‐year outcomes of outpatients and inpatients with heart failure (HF). The pilot phase was also specifically aimed at validating structure, performance, and quality of the data set for continuing the survey into a permanent Registry.

EURObservational Research Programme: The Heart Failure Pilot Survey (ESC-HF Pilot)

The primary objective of the new ESC‐HF Pilot Survey was to describe the clinical epidemiology of outpatients and inpatients with heart failure (HF) and the diagnostic/therapeutic processes applied across 12 participating European countries. This pilot study was specifically aimed at validating the structure, performance, and quality of the data set, for continuing the survey into a permanent registry.

Inflammatory cytokines and the possible immunological role for lipoproteins in chronic heart failure.

AIMS We studied the clinical and immunological importance of fasting cholesterol, HDL, LDL and triglycerides in patients with chronic heart failure in relation to plasma concentrations of tumor necrosis factor-alpha (TNFalpha), soluble TNF receptor-1 and -2 (sTNF-R1 and -R2), and a ratio potentially indicating recent endotoxin bioactivity (soluble [s] CD14/total cholesterol). METHODS AND RESULTS Fifty-eight stable, non-oedematous patients with established heart failure and 19 controls were studied prospectively. Concentrations of sTNF-R1 and sCD14 were higher in patients than in controls (1238+/-96 vs. 632+/-72 pg/ml, P=0.005 and 3401+/-120 vs. 2775+/-139 pg/ml, P=0.007, respectively), whereas those of TNFalpha (9.3+/-1.1 vs. 6.7+/-0.6 pg/ml) and sTNF-R2 (2464+/-145 vs. 1920+/-303 pg/ml) were not. Cholesterol (5.6+/-0.1 vs. 5.5+/-0.2 mmol/l) and LDL (3.5+/-0.1 vs. 3.6+/-0.2 mmol/l) were not different (both P>0.75). Patients had lower HDL (1.10+/-0.04 vs. 1.4+/-0.06 mmol/l, P=0.0004) and higher triglycerides (2.1+/-0.1 vs. 1.1+/-0.1 mmol/l, P=0.0006). Aetiology and the presence of cardiac cachexia did not influence the lipid profile. Correlations in patients: cholesterol vs. TNFalpha (r=-0.40, P=0.003), vs. sTNF-R1 (r=-0.24, P=0.08), vs. sTNF-R2 (r=-0.29, P<0.04); sCD14 vs. TNFalpha (r=0.44, P=0.005), vs. sTNF-R1: (r=0.65, P<0.0001), vs. sTNF-R2 (r=0.59, P<0. 0001). The sCD14/cholesterol ratio related powerfully to TNFalpha (r=0.60), sTNF-R1 (r=0.74), and sTNF-R2 (r=0.65, all P<0.0001). This sCD14/cholesterol ratio emerged as the strongest predictor of TNFalpha, sTNF-R1 and -R2 (all P<0.01), independently of renal and hepatic function, and conventional measures of disease severity. A cholesterol level <5.2 mmol/l (n=18) significantly predicted a poor clinical outcome (P<0.04, RR 3.5, 95% CI 1.1-11.0) independently of peak VO(2) (P=0.07), NYHA class (P=0.08), aetiology (P=0.14), and age, body wasting, sodium, LVEF, heart rate, and blood pressure (all P>0.20, follow-up 12 months, event rate 26%). CONCLUSION Our data supports previous findings that lower, rather than higher cholesterol levels are associated with poor clinical outcome in patients with chronic heart failure. This relationship is unrelated to heart failure aetiology, and suggests that the classic risk profile is not longer relevant in established heart failure. The little-recognised ability of all lipoprotein fractions to bind endotoxin and to serve as natural buffer substances may explain this relationship between lower lipoprotein levels, higher cytokine concentrations and impaired prognosis.

Reduced Peripheral Skeletal Muscle Mass and Abnormal Reflex Physiology in Chronic Heart Failure

Background— The muscle hypothesis implicates abnormalities in peripheral muscle as a source for the stimulus to the symptoms and reflex abnormalities seen in chronic heart failure (CHF). We investigated the relationship between skeletal muscle mass (with dual-energy x-ray absorptiometry) and activation of the ergoreflex (a peripheral reflex originating in skeletal muscle sensitive to products of muscle work) in CHF patients and whether this rapport is affected by the progression of the syndrome. Methods and Results— We assessed 107 consecutive CHF patients (mean age, 61.9±10.9 years; 95% male; 25 cachectics) and 24 age-matched normal subjects (mean age, 59.0±11.1 years; 91% male). Compared with normal subjects, patients had a higher ergoreflex (in ventilation, 6.2±.6.1 versus 0.6±0.6 L/min; P<0.0001) and a reduction in muscle mass (51.9±10.0 versus 60.3±8.8 kg; P<0.001). The ergoreflex was particularly overactive in cachectics (P<0.05), accompanied by marked muscle mass depletion (P<0.0005). In CHF, ergoreceptor hyperresponsiveness in both the arm and leg correlated with reduced muscle mass, abnormal indexes of exercise tolerance (peak &OV0312;o2, &OV0312;e/&OV0312;co2 slope), ejection fraction, and NYHA functional class (P<0.0001). In the cachectic population, the ventilatory response from ergoreflex to arm exercise was strongly inversely correlated with arm (r=−0.65), leg (r=−0.64), and total (r=−0.61) lean tissues (P<0.001 for all). Multivariate analysis showed that these relationships were independent of NYHA class, peak &OV0312;o2, and &OV0312;e/&OV0312;co2 slope. Conclusions— Depleted peripheral muscle mass is associated with ergoreflex overactivity and exercise limitation in CHF, particularly in cachectic patients. The systemic activation of the muscle reflex system in CHF may reflect progression and deterioration of the clinical syndrome.

Insights into the pathogenesis of chronic heart failure: immune activation and cachexia.

Body wasting, i.e, cardiac cachexia, is a complication of chronic heart failure (CHF). The authors have suggested that cardiac cachexia should be diagnosed when nonedematous weight loss of more than 7.5% of the premorbid normal weight occurs over a time period of more than 6 months. In an unselected CHF outpatient population, 16% of patients were found to be cachectic. The cachectic state is predictive of poor survival independently of age, functional class, ejection fraction, and exercise capacity. Patients with cardiac cachexia suffer from a general loss of fat, lean, and bone tissue. Cachectic CHF patients are weaker and fatigue earlier. The pathophysiologic causes of body wasting in patients with CHF remain unclear, but initial studies have suggested that humoral neuroendocrine and immunologic abnormalities may be of importance. Cachectic CHF patients show increased plasma levels of catecholamines, cortisol, and aldosterone. Several studies have shown that cardiac cachexia is linked to increased plasma levels of tumor necrosis factor alpha. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. Some investigators have suggested that endotoxin may be important in triggering immune activation in CHF patients. Available studies suggest that cardiac cachexia is a multifactorial neuroendocrine and immunologic disorder that carries a poor prognosis. A complex catabolic-anabolic imbalance in different body systems may cause body wasting in patients with CHF.