The value of cardiopulmonary exercise testing and brain natriuretic peptide plasma levels in predicting the prognosis of patients with chronic heart failure.

BACKGROUND: A peak VO2 above 14 ml/min/kg at cardiopulmonary exercise testing and brain natriuretic peptide (BNP) levels is used to estimate survival in patients with chronic heart failure (CHF). Limited data, however, exist comparing the prognostic value of both markers simultaneously in patients with mild to moderate CHF. METHODS: We prospectively studied 85 consecutive patients (59+/-13 years, 63 men) with CHF (mean LVEF 26+/-6%). All patients underwent cardiopulmonary exercise testing with determination of peak VO2 and measurement of plasma BNP at rest. The incidence of cardiac decompensation and cardiac death was recorded in the follow-up. RESULTS: During a mean follow-up of 427+/-150 days, four deaths and ten cardiac decompensations occurred. Kaplan-Meier estimates of freedom from clinical events differed significantly for patients above and below the median BNP of 292 pg/ml and also for patients above and below a peak VO2 of 14 ml/min/kg (p<0.05 each). BNP and peak VO2 (area under the ROC 0.75 vs. 0.72) showed a comparable discrimination of CHF patients with adverse cardiac events. The prognostic information of BNP was at least as powerful as that derived from peak VO2. A BNP above 324 pg/ml was associated with a risk ratio of 8.8 for adverse cardiac events. CONCLUSIONS: In patients with mild to moderate CHF, BNP measurements appear to be an alternative to peak VO2 determined by cardiopulmonary exercise testing for the assessment of prognosis in CHF. BNP may facilitate the ambulatory management of patients with mild to moderate CHF since it is less expensive, less time-consuming, and free of procedural risk compared to exercise testing.

brain natriuretic peptide levels predict functional capacity in patients with chronic heart failure.

OBJECTIVES: The goal of this study was to determine if brain natriuretic peptide (BNP) levels are associated with exercise capacity in patients with chronic heart failure (HF). BACKGROUND: Plasma levels of BNP are increased subject to the degree of systolic and diastolic left ventricular dysfunction in patients with chronic HF. Exercise testing is useful to assess functional capacity and prognosis in chronic HF. METHODS: We prospectively studied 70 consecutive patients with chronic HF (60.3 +/- 10.4 years, 51 men) referred for cardiopulmonary exercise testing. Resting BNP was obtained after 10 min of supine rest before symptom-limited bicycle exercise testing. RESULTS: In patients with chronic HF, BNP levels correlated with oxygen uptake (VO(2)), both at anaerobic threshold (VO(2)AT: r = -0.54, p < 0.001) and peak exercise (peak VO(2): r = -0.56, p < 0.001). Impairment of ventilatory efficiency (EqCO(2): r = 0.43, p < 0.001) and maximum exercise level (W % predicted: r = -0.44, p < 0.05) correlated less well with BNP. There was a significant inverse correlation between left ventricular ejection fraction and BNP (r = -0.50, p < 0.05). Brain natriuretic peptide discriminated well chronic HF patients with a peak VO(2) <10 ml/min/kg (area under the receiver operating characteristic [ROC] 0.93) or <14 ml/min/kg (area under the ROC 0.72). A BNP >316 pg/ml was associated with a risk ratio of 6.8 (95% confidence interval, 2.3 to 19.8) for a reduced exercise capacity with a peak VO(2) <14 ml/min/kg. CONCLUSIONS: Brain natriuretic peptide is clearly associated with exercise capacity in chronic HF. Brain natriuretic peptide levels show a significant correlation with the impairment of VO(2) at peak exercise and anaerobic threshold. Brain natriuretic peptide is able to differentiate between chronic HF patients with moderately and severely impaired exercise capacity.

Urotensin II in patients with chronic heart failure.

BACKGROUND: Human Urotensin II (hU-II) is the most potent vasoconstrictor known to date. HU-II receptors are predominant in the human heart and arterial vessels, suggesting hU-II to be of importance as a cardiovascular mediator. METHODS: We studied 32 consecutive patients (60+/-12 years) with chronic heart failure (CHF) and 10 control subjects (54+/-12 years, n.s.) with cardiopulmonary exercise testing. Blood samples for the measurement of plasma hU-II and big-endothelin-1 (big-ET1) were obtained at rest and at peak exercise. RESULTS: Peak VO(2) was significantly higher in controls than in CHF patients (19.8+/-3.8 vs. 14.7+/-3.6 ml min(-1) kg(-1), P<0.001). Big-ET1 levels were increased in CHF compared to controls at rest (2.8+/-1.8 vs. 1.7+/-0.1 fmol/ml, P<0.01) and at peak exercise (2.7+/-1.7 vs. 1.6+/-0.2 fmol/ml, P<0.005). HU-II concentrations were comparable in patients with CHF and controls at rest (2990+/-1104 vs. 3290+/-508 pg/ml, n.s.) and peak exercise (3063+/-1185 vs. 3213+/-1188 pg/ml, n.s.). Resting hU-II levels demonstrated no correlation with peak VO(2) in controls or CHF patients. CONCLUSIONS: The measurement of circulating plasma levels of hU-II does not seem to be very helpful in studying the effects of hU-II in human cardiovascular regulation. A local paracrine or autocrine mediator effect of hU-II in CHF is possible.

CD14 gene -260 C/T polymorphism is associated with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) show inflammatory changes and elevated plasma levels of TNFalpha and endotoxins. However, the role of the CD14 C(-260)T polymorphism in patients with CHF is unclear. Therefore, we sought to determine whether the C=>T promoter polymorphism (position -260) of the CD 14 gene is associated with a higher risk for the development of CHF. METHODS: We studied 100 patients with CHF (mean age 62+/-3 years, LVEF 28+/-8%) and 100 healthy controls (59+/-10 years, p=NS; LVEF 60+/-4%, p<0.05). CD14 genotyping was performed using a PCR-RFLP technique. RESULTS: Among CHF patients, the frequency of the T allele was lower (38% vs. 48%, p<0.05) and the frequency of the C allele higher (62 % vs. 52 %, p<0.05) than among controls. The distribution of CD14 genotypes in healthy controls was as follows: CC 32%, CT 40%, and TT 28%. Among CHF patients, the TT genotype was significantly underrepresented compared to controls: CC 38%, CT 48%, and TT 14% (p<0.05). CONCLUSIONS: The C -260T polymorphism of CD14 seems to influence the susceptibility for the development of CHF. The T allele is less frequent among CHF patients than among controls. The TT genotype could be a new genetic protective factor against the development of CHF.

Endotoxin sensitivity and immune competence in chronic heart failure.

BACKGROUND: Raised concentrations of endotoxin (lipopolysaccharide, LPS) are found in patients with chronic heart failure (CHF). Tolerance of monocytes to LPS can be induced by LPS itself resulting in a downregulation of cytokine response to LPS challenge. This phenomenon of LPS desensitization has also been suggested for CHF. METHODS: We investigated whether CHF patients really show a desensitization to LPS stimuli at rest or after physical exercise, which was used as a model of limited inflammatory reaction. Thirty-five patients with CHF (59+/-12 years, 8 women) and 30 healthy control subjects were prospectively studied with cardiopulmonary exercise testing. At rest and directly after exercise blood samples were taken for the quantitative determination of HLA-DR expression of monocytes as a measure for immune competence and for the measurement of TNFalpha generation after ex vivo stimulation by LPS. RESULTS: HLA-DR expression was comparable in CHF patients and controls at rest as well as after exercise. TNFalpha production by LPS-stimulated monocytes ex vivo was higher in CHF patients compared to controls at rest and after exercise. CONCLUSIONS: Thus, our data are the first to show that patients with stable CHF show a cellular hypersensitivity to LPS with a higher TNFalpha generation capacity at rest and after exercise compared to controls. CHF patients seem to have a marked susceptibility to low inflammatory stimuli and no desensitization to LPS.

Brain natriuretic peptide kinetics during dynamic exercise in patients with chronic heart failure.

BACKGROUND: The kinetics of brain natriuretic peptide (BNP) secretion in chronic heart failure (CHF) during dynamic exercise have been the subject of controversial debate. The present study was therefore aimed to further clarify whether marked changes in BNP levels occur during and directly after vigorous exercise in CHF patients. METHODS: We prospectively studied 37 patients with CHF (60+/-10 years, LVEF 26+/-6%) and 20 healthy controls (58+/-11 years, LVEF 60+/-3%). Standardized exercise testing was performed in all CHF patients and controls. Venous blood samples for measurement of BNP were obtained prior to symptom-limited exercise, at peak exercise and at 1 and 5 min of recovery time. RESULTS: BNP concentrations were significantly higher in CHF compared to controls at rest, peak exercise and at 1 and 5 min of recovery. BNP levels did not change significantly during exercise in the control group. In CHF patients, BNP levels showed no marked difference at rest (428+/-421 pg/ml), peak exercise (507+/-450 pg/ml, n.s.), 1 min (560+/-460 pg/ml, n.s.) and 5 min recovery (526+/-424 pg/ml, n.s.). Strikingly, 6 of 37 CHF patients (16%) showed a decrease in BNP at exercise compared to rest but none of the controls. CONCLUSIONS: BNP levels in CHF patients and healthy controls are not significantly altered by vigorous exercise. In contrast to controls, 16% of CHF patients showed a decrease in BNP levels at exercise. In CHF, BNP levels were inversely correlated with peak VO(2), VO(2)-AT and LVEF.

Endotoxin hypersensitivity in chronic heart failure.

BACKGROUND: Raised concentrations of endotoxin (lipopolysaccharides, LPS) have been demonstrated in patients with chronic heart failure (CHF). Tolerance of monocytes to LPS can be induced by negative feedback mechanism through LPS itself, resulting in a downregulation of cytokine response to LPS challenge. As endotoxin desensitization has also been suggested for CHF, we investigated the response to LPS challenge in CHF patients. METHODS: We prospectively studied 100 patients with CHF (62 +/- 13 years) and 21 controls (58 +/- 10 years, LVEF 60 +/- 3%). HLA-DR expression and TNFalpha generation of monocytes after ex vivo stimulation by LPS (stimulation with LPS 50 and 500 pg/ml) were determined. 46 CHF patients were in NYHA class II (LVEF 29 +/- 8%) and 54 in NYHA class III (LVEF 27 +/- 7%). RESULTS: HLA-DR expression in controls (25,837 +/- 7915 ABS/cell) was comparable to CHF NYHA II patients (23,720 +/- 8488 ABS/cell, n.s.), but lower in patients classified NYHA III (20,327 +/- 5073 ABS/cell, p < 0.01). Stimulated TNFalpha production ex vivo was higher in CHF NYHA III (LPS 50: 437 +/- 284; LPS 500: 946 +/- 500 pg/ml, each p < 0.05) and CHF NYHA II (LPS 50: 397 +/- 277; LPS 500: 933 +/- 483 pg/ml, each p < 0.05) compared to controls (LPS 50: 315 +/- 134; LPS 500: 715 +/- 339 pg/ml). CONCLUSIONS: In chronic heart failure TNFalpha generation capacity increases while HLA-DR expression decreases compared to controls. Thus patients with CHF display enhanced susceptibility to inflammatory stimuli.

Relaxin kinetics during dynamic exercise in patients with chronic heart failure.

Background: We investigated circulating relaxin (RLX) and its potential role in human congestive heart failure (CHF) at rest and after physical exercise. Methods: A total of 10 healthy controls and 35 patients with stable CHF were enrolled in the study. Results: RLX plasma concentrations at rest and after exercise were comparable in patients with CHF and in controls. Conclusion: These findings suggest that RLX does not play a major role as a circulating hormone in human CHF.