Aidan P. Bolger

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 (FEV1) recorded at the start of the study was 1.8 (1.0) l (52 (26)% predicted FEV1), 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). FEV1, % predicted FEV1, Pao 2, % ideal weight (all p<0.0001), and Paco 2 (p=0.04) predicted survival. In multivariate analysis, % predicted FEV1 (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 ⩽85% ideal weight (survival 53%, 95% CI 45 to 62), p<0.0001. Percentage predicted FEV1 (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.

Effect of anemia on exercise tolerance in chronic heart failure in men

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Congenital heart disease: the original heart failure syndrome

Heart failure is characterised by a triad comprising cardiac abnormality, exercise limitation and neurohormonal activation. The 2% of the adult population who suffer with heart failure are known to derive both symptomatic and prognostic benefit from exercise and pharmacologic neurohormonal antagonism. The existence of heart failure has traditionally been considered in the context of ischaemic, hypertensive, valvular and myopathic disease but in this article we develop the argument that patients with congenital heart disease also manifest all the pathophysiological criteria that constitute the chronic heart failure syndrome. We discuss the inherent limitations to a purely anatomical approach to congenital heart disease, bring attention to the large and rapidly growing population of adults with this condition and conclude by calling for a therapeutic approach to congenital heart disease that is based on the heart failure paradigm.

The regulation and measurement of plasma volume in heart failure

Plasma volume, the intravascular portion of the extracellular fluid volume, can be measured using standard dilution techniques with radiolabeled tracer molecules. In healthy persons, plasma volume remains relatively constant as a result of tight regulation by the complex interaction between neurohormonal systems involved in sodium and water homeostasis. Although chronic heart failure (CHF) is characterized by activation of many of these neurohormonal systems, few studies have evaluated plasma volume in this condition under treatment. Untreated edematous decompensated heart failure (HF) is associated with a significant expansion of plasma volume. Patients with stable CHF, receiving conventional therapy, appear to have a contracted plasma volume, a concept that is in contrast to the widely held belief that CHF is associated with long-term hypervolemia. It is likely that significant changes in plasma volume occur during intensification of medical therapy or during transition from the edematous to the stable state. Clinical assessment of plasma volume may be of particular value during treatment in patients with decompensated HF, in whom the plasma volume is contracted despite an increase in total extracellular fluid volume. Under these circumstances, treatment with inotropes or renal vasodilators may be more appropriate than intravenous diuretics alone. Further studies evaluating plasma volume in HF may help to improve our understanding of the pathophysiologic mechanisms occurring in the development and progression of this complex condition.

Usefulness of natriuretic peptide levels to predict mortality in adults with congenital heart disease

Neurohormonal activation is prevalent in adults with congenital heart disease, but its relation to outcome remains unknown. B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) were measured prospectively in 49 patients with adult congenital heart disease, who were followed up for a median of 7.9 years (interquartile range 7.7 to 8.2). Cox proportional hazards regression analysis was used to determine the relation of BNP and ANP concentrations to all-cause mortality. The mean age at baseline was 33.9 +/- 11.3 years, and 46.9% of patients were men. Most patients (77.5%) were symptomatic (20.4% had New York Heart Association class III), 10 (20.4%) were cyanotic, and 28 (57.1%) had systemic ventricular dysfunction (moderate or severe in 18.4%). The median concentration of BNP was 52.7 pg/ml (interquartile range 39.1 to 115.4) and of ANP was 47.4 pg/ml (interquartile range 19.7 to 112.8). Of the 49 patients, 11 (22.4%) died during the follow-up period. Both BNP and ANP were strong predictors of mortality (hazard ratio per 100-pg/ml increase 1.80, 95% confidence interval 1.38 to 2.34, p <0.0001; and hazard ratio per 100-pg/ml increase 1.21, 95% confidence interval 1.12 to 1.32, p <0.0001, respectively). A BNP value >78 pg/ml predicted death with a sensitivity of 100% and specificity of 76.3% (area under the curve 0.91, p = 0.0001). An ANP value of >146 pg/ml predicted death with a sensitivity of 72.7% and specificity 94.7% (area under the curve 0.89, p = 0.0001). No patients with a BNP level <78 pg/ml died during the follow-up period. In conclusion, the BNP and ANP levels strongly predicted death in symptomatic ambulatory patients with adult congenital heart disease during mid-term follow-up and could be used as a simple clinical marker for risk stratification in this population.

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, β-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.

Effect of interleukin-10 on the production of tumor necrosis factor-alpha by peripheral blood mononuclear cells from patients with chronic heart failure

Chronic heart failure (HF) is a state of inflammatory immune activation characterized by elevated circulating levels of tumor necrosis factor-alpha (TNF-alpha). Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that inhibits TNF-alpha production and lessens endotoxin bioactivity. It is not known whether IL-10 reduces lipopolysaccharide (LPS) stimulated TNF-alpha production of peripheral blood mononuclear cells (PBMCs) from patients with chronic HF. PBMCs were isolated from 15 patients with chronic HF (New York Heart Association functional class 3.0 +/- 0.2, left ventricular ejection fraction 30 +/- 2%, peak oxygen consumption 18.1 +/- 0.8 ml/kg/min) and 15 healthy control subjects and stimulated with 1 and 10 ng/ml LPS for 24 hours with or without prior addition of IL-10 (10 ng/ml). TNF-alpha was quantified in cell-free supernatants by an enzyme-linked immunosorbent assay. TNF-alpha, soluble TNF receptors, IL-10, and LPS were quantified in plasma. LPS stimulated TNF-alpha production was highest in those patients in New York Heart Association class II (p <0.01 vs New York Heart Association class III and IV, p <0.001 vs control subjects). IL-10 reduced PBMC TNF-alpha production in all stimulated samples at 1 and 10 ng/ml LPS (mean reduction 43% at 1 ng/ml, p <0.01 and 55% at 10 ng/ml, p <0.0001). The percentage reduction in TNF-alpha release did not differ significantly between patients and control subjects or with respect to severity of chronic HF or baseline immune parameters. Independently of clinical severity, IL-10 profoundly inhibits TNF-alpha release from PBMCs isolated from patients with chronic HF. IL-10 is, therefore, a potential therapy for use in chronic HF associated with inflammatory immune activation.

Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure

Bacterial endotoxin activity is elevated in patients with decompensated chronic heart failure (HF) and acts as a potent stimulus for immune activation. We sought to determine whether endotoxin, at an activity level seen in vivo (around 0.6 EU/ml), is sufficient to stimulate the secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha soluble receptor (sTNFR2) in ex vivo whole blood from patients with HF. We studied 15 patients with HF (aged 65 +/- 1.9 years, New York Heart Association class 2.1 +/- 0.3, left ventricular ejection fraction 31 +/- 5%; mean +/- SEM), of whom 5 had cardiac cachexia, and 7 healthy control subjects (59 +/- 5 years, p = NS). Reference endotoxin was added to venous blood at concentrations of 0.6, 1.0, and 3.0 EU/ml, and was incubated for 6 hours. Endotoxin induced a dose-dependent increase in TNF-alpha release (p <0.05 in all groups). Patients with noncachectic HF produced significantly more TNF-alpha compared with controls after stimulation with 0.6, 1.0, and 3.0 EU/ml of endotoxin (113 +/- 46 vs 22 +/- 4 [p = 0.009], 149 +/- 48 vs 34 +/- 4 [p = 0.002], and 328 +/- 88 vs 89 +/- 16 pg/ml [p = 0.002], respectively; mean +/- SEM). Patients with cardiac cachexia produced significantly less TNF-alpha compared with patients without cardiac cachexia for all given concentrations (all p <0.05, analysis of variance p = 0.02). Production of sTNFR2 was greater at all concentrations of endotoxin versus controls (all p <0.05, analysis of variance p = 0.002). Plasma endotoxin levels were higher in patients with cardiac cachexia (4.3 times higher than in control subjects, p <0.005). Thus, low endotoxin activity, at levels seen in vivo in patients with HF, induces significant TNF-alpha and sTNFR2 production ex vivo. These results suggest that elevated plasma endotoxin activity observed in patients with HF is of pathophysiologic relevance.

Clinical characteristics and survival of patients with chronic heart failure and prolonged QRS duration.

BACKGROUND Abnormal prolongation of QRS duration is a common finding in patients with chronic heart failure, and is associated with an impaired prognosis. The optimum QRS duration for separating chronic heart failure patients with respect to prognosis has not been determined. Whilst resynchronisation of ventricular conduction may benefit patients with QRS>150 ms, this has yet to be determined for patients with moderate QRS prolongation. METHODS We evaluated 155 patients with chronic heart failure (New York Heart Association class 2.6+/-0.8, mean+/-S.D.). The mean follow-up period was 838+/-748 days. Patients were sub-grouped according to QRS duration: <120 ms (normal QRS, n=82), 120-150 ms (moderate prolongation, n=44) and >150 ms (severe prolongation, n=29). RESULTS The optimal QRS duration for stratifying patients for 2-year event free survival was 120 ms (receiver operating characteristic analysis: area under curve 0.73; 95% CI 0.64-0.81). Moderate prolongation of QRS duration was associated with a worse New York Heart Association class, peak oxygen consumption and left ventricular ejection fraction when compared to patients with normal QRS duration (all P<0.05). Patients with moderate prolongation of QRS duration had similar impairment of New York Heart Association class and peak oxygen consumption as compared with patients with QRS duration >150 ms (all P>0.05). CONCLUSIONS The optimum QRS duration for stratifying patients for medium to long-term event-free survival was 120 ms. Heart failure patients with moderate QRS prolongation share similar impairment of exercise capacity and functional class to those with severe prolongation.

Whole blood endotoxin responsiveness in patients with chronic heart failure: the importance of serum lipoproteins

Endotoxin [lipopolysaccharide (LPS)] may be an important stimulus for cytokine release in patients with chronic heart failure (CHF). We sought to investigate the relationship between whole blood endotoxin responsiveness and serum lipoprotein concentrations. It is not known if low‐dose LPS is sufficient to stimulate immune activation.