Is plasma N‐BNP a good indicator of the functional reserve of failing hearts? The FRESH‐BNP study

AIMS: Whether plasma N-terminal brain natriuretic peptide (N-BNP) is useful in the diagnosis of heart failure (HF) depends traditionally on whether it is as good as the putative 'gold-standard', left ventricular ejection fraction (LVEF), in indicating cardiac dysfunction. However, since HF is primarily an impairment of function of the cardiac pump, we explored the relationship between N-BNP and direct and indirect indicators of cardiac pump dysfunction. METHODS AND RESULTS: Eighty-six HF patients (mean age 56 years) with a range of LVEF's (mean 36.9+/-15.2%, range 15-66%) and 10 age-matched healthy controls were recruited into the study and had resting N-BNP measured. Cardiopulmonary exercise testing was performed to assess peak oxygen consumption (Vo(2)). A subgroup of 23 subjects underwent further exercise haemodynamic assessment to evaluate peak cardiac power output (CPO). The CHF group had significantly higher N-BNP (median [interquartile range]) levels (299 [705] fmol/ml) than the control group (7 [51] fmol/ml, P<0.005). Significant correlations between N-BNP and peak Vo(2), and N-BNP and peak CPO were observed (R> or =0.5, P<0.005). Although significant correlation was observed between N-BNP and LVEF (R=0.34, P=0.01), the correlations between LVEF and peak Vo(2) or peak CPO (all R<0.3, P>0.3) were not significant. Multivariate analysis identified plasma N-BNP and NYHA class, but not LVEF, as independent predictors of peak Vo(2). CONCLUSIONS: We have found that N-BNP was surprisingly good as a simple indicator of cardiac pump dysfunction. Since heart failure is an inadequacy of function, these results strongly support the notion that N-BNP is a useful blood test in estimating the extent of cardiac pump dysfunction and helpful in establishing positive diagnosis of heart failure.     

Plasma endothelin-1 levels and clinical correlates in patients with chronic heart failure

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, and patients with chronic heart failure (CHF) are reported to have high plasma ET-1 levels. The aim of this study was to investigate the relation between plasma ET-1 levels and clinical correlates in patients with CHF. The effects of maximal exercise on plasma ET-1 levels were also investigated. METHODS: Plasma concentrations of ET-1, norepinephrine, and atrial and brain natriuretic peptide (ANP and BNP) both at rest and after maximal cardiopulmonary exercise test were determined in 100 patients with CHF (60 +/- 12 years, New York Heart Association [NYHA] class I-III, left ventricular ejection fraction [LVEF]=36 +/- 8%, peak oxygen uptake [VO2] = 18.2 +/- 5.0 mL/min/kg) and 27 controls. RESULTS: Patients with NYHA class II and III CHF had higher ET-1 levels (controls, NYHA class I, II, III: 2.1 +/- 0.6, 2.1 +/- 1.0, 2.6 +/- 0.9, 3.4 +/- 0.8 pg/mL, analysis of variance P <.0001). Maximal exercise did not alter ET-1 levels in controls or in each CHF subgroup. When all CHF patients were analyzed together, cardiothoracic ratio (P<.01), peak VO2 (P<.001), plasma norepinephrine (P<.01), plasma ANP (P<.01), and plasma BNP (P<.001) were significantly related with resting ET-1 levels on univariate analysis. Multivariate analysis revealed peak VO2 and plasma BNP levels showed an independent and significant relationship with the resting plasma ET-1 levels. CONCLUSIONS: Resting ET-1 levels were increased in symptomatic patients with CHF, and maximal exercise did not increase ET-1 levels. Peak VO2 and plasma BNP levels were independently associated with resting plasma ET-1 levels in patients with CHF.     

The role of exercise ventilation in clinical evaluation and risk stratification in patients with chronic heart failure

BACKGROUND: Patients with chronic heart failure (CHF) are characterised by an increased ventilatory response to exercise. The role of exercise ventilation in the risk stratification and evaluation of patients with CHF has not yet been established. AIM: To examine the relationship between exercise ventilation indices and clinical parameters of CHF and to assess the prognostic value of the ventilatory response to exercise. METHODS: The study group consisted of 87 patients with CHF (72 males, mean age 58 years) with a mean left ventricular ejection fraction of 32%. Ten patients were in NYHA class I, 38 - in NYHA class II, 34 - in NYHA class III, and 5 - in NYHA class IV. The control group consisted of 20 patients without CHF (13 males, mean age 58 years, mean LVEF - 61%). All studied subjects underwent maximal exercise test with gas-exchange measurement. The following parameters were analysed: peak exercise oxygen consumption [peak VO(2) (ml/kg/min)], VE-VCO(2) index [a coefficient of linear regression analysis depicting an association between ventilation (VE) and carbon dioxide production (VCO(2)) during exercise] and VE/VCO(2) ratio at peak exercise to VE/VCO(2) ratio while at rest (VE/VCO(2 peak/rest)). RESULTS: Ventilatory response indices were significantly higher in patients with CHF compared with controls: VE-VCO(2) - 37.9+/-11.1 vs 27.1+/-4.1; VE-VCO(2 peak/rest) - 0.89+/-0.14 vs 0.75+/-0.10 (p<0.001). In CHF patients a significant positive correlation between ventilatory response parameters and NYHA class (VE-VCO(2) - r=0.52; VE/VCO(2 peak/rest) - r=0.47) and a negative correlation with peak VO(2) (VE-VCO(2) - r=-0.52; VE/VCO(2 peak/rest) - r=-0.49) were noted (p<0.0001 for all correlations). No correlation was found between ventilatory parameters and echocardiographic variables or CHF aetiology. During the follow-up period lasting at least 12 months, 17 (22%) patients died. In the univariate Cox model, NYHA class III-IV, decreased peak VO(2) and increased VE-VCO(2) and VE/VCO(2 peak/rest) values were significantly associated with the risk of death. The multivariate analysis revealed that VE/VCO(2 peak/rest) > or =1.0 was the adverse prognostic factor, independent of peak VO(2) (p=0.02) and NYHA class (p=0.01). The Kaplan-Meier analysis showed that prognosis during the 18-month follow-up period in patients with enhanced exercise ventilation was worse than in the remaining patients (59% survival in patients with VE/VCO(2 peak/rest) > or =1.0 59% vs 91% survival in patients with VE/VCO(2 peak/rest) <1.0, p=0.001). CONCLUSIONS: In patients with stable CHF simple exercise ventilation parameters may provide important clinical and prognostic information.     

Ischemic etiology of heart failure identifies patients with more severely impaired exercise capacity

BACKGROUND: Peak oxygen uptake (peak VO2) and the regression slope of ventilation against CO2 production during exercise (VE/VCO2 slope) are powerful prognostic indicators in patients with chronic heart failure (CHF). Our purpose was to evaluate the influence of CHF etiology on peak VO2 and VE/VCO2 slope, independently of demographic, clinical, Doppler-echocardiographic and neurohormonal factors. METHODS: Data were collected from 239 CHF patients referred for a cardiopulmonary exercise test as part of their clinical evaluation. Patients were stratified according to their CHF etiology (ischemic versus non-ischemic). RESULTS: The etiology of heart failure was ischemic in 143 patients (60%) and non-ischemic in 96 (40%). Patients with ischemic etiology, compared with those with non-ischemic etiology, showed a lower peak VO2 (15.4+/-4.2 versus 17.8+/-4.8 ml/kg/min, p<0.0001) and a steeper VE/VCO2 slope (38.1+/-6.8 versus 34+/-5.3, p<0.0001). In the univariate model, age (r=-0.36, p<0.0001), female sex (r=-0.21, p=0.001), ischemic CHF etiology (r=-0.26, p<0.0001) and NYHA class (r=-0.52, p<0.0001) correlated with peak VO2. At multivariate analysis, ischemic CHF etiology (beta=-0.23, p=0.001) was a predictor of peak VO2 (R(2)=0.49) independently of age (beta=-0.23, p=0.001), female sex (beta=-0.25, p=0.0006) and NYHA class (beta=-0.31, p<0.0001). Similarly, ischemic etiology (beta=0.29, p=0.001) predicted the VE/VCO2 slope (R(2)=0.38) independently of E/A ratio (beta=0.27, p=0.01) and resting heart rate (beta=0.22, p=0.01). CONCLUSIONS: Etiology of heart failure may influence the functional capacity and the ventilatory response to exercise.     

Comparison of plasma N-brain natriuretic peptide, peak oxygen consumption, and left ventricular ejection fraction for severity of chronic heart failure

We investigated whether a simple blood test of plasma N-brain natriuretic peptide (N-BNP), compared with echocardiographic left ventricular ejection fraction (LVEF), both measured at rest, correlated well with aerobic exercise capacity (peak oxygen consumption [VO₂]) in patients with chronic heart failure. Plasma N-BNP was found to significantly correlate with peak VO₂ (p <0.001) and exercise duration (p = 0.001), whereas LVEF showed very poor correlations with peak VO₂ and exercise duration (both p >0.3). The results suggest that N-BNP actually reflects functional cardiac impairment better than LVEF.     

Early expression of natriuretic peptides and SERCA in mild heart failure: association with severity of the disease

BACKGROUND: We investigated changes in genetic expression of atrial and brain natriuretic peptides (ANP and BNP) and sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) in patients with stable mild to moderate chronic heart failure (CHF), since data on this topic were primarily obtained in end-stage CHF. METHODS: We studied tissue from 25 patients with idiopathic dilated cardiomyopathy (IDC) in New York Heart Association (NYHA) class II (n=12) and III-IV (n=13). Myocardial tissue from normal hearts (n=10) served as controls. Messenger RNA (mRNA) expression of ANP, BNP, and SERCA was isolated, and correlated with severity of CHF, left ventricular function (LVEF), peak oxygen uptake (peak VO(2)), and wedge pressure. RESULTS: A significant trend for gradual changes in mRNA expression according to increasing NYHA class was found for ANP, BNP (P<0.0001) and SERCA (P=0.04), with a marked increase in patients with more advanced CHF (ANP and BNP: P<0.01 vs. controls; SERCA: NS) and less pronounced changes in patients with mild CHF. mRNA of ANP and BNP correlated strongly with LVEF (-0.621 and -0.621, respectively, both P<0.01) and peak VO(2) (-0.625 and -0.555, respectively, both P<0.01) and, to a lesser extent, with wedge pressure (0.440 and 0.488, respectively, both P<0.05). SERCA correlated most strongly with wedge pressure (-0.623, P<0.01), and weak, non-significant correlations with LVEF and peak VO(2) were found. CONCLUSIONS: Genetic expression of ANP, BNP, and SERCA is progressively altered in proportion to the severity of CHF, although this is more marked for ANP and to a lesser extent BNP, than for SERCA. These changes support the concept that already early in CHF, genetic expression is affected, which has implications for the understanding of the pathophysiology of CHF.     

Interleukin-6 and tumor necrosis factor-alpha levels increase in response to maximal exercise in patients with chronic heart failure

Chronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. Strenuous exercise causes activation of both systems but the effect of acute bouts of exercise on cytokines is not known in patients with CHF. This study determined whether maximal exercise induces activation of cytokines in CHF. Plasma interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, epinephrine, norepinephrine, and atrial and brain natriuretic peptides (ANP and BNP) were determined before and after symptom-limited cardiopulmonary exercise testing in 80 patients with CHF (LVEF=38+/-1%, peak VO(2)=18.8+/-0.5 ml/min/kg) and age-matched 33 controls. Resting IL-6 (Controls vs. CHF: 1.3+/-0.2 vs. 2.5+/-0.3 pg/ml, P<0.001) and TNF-alpha (2.7+/-0.2 vs. 3.8+/-0.2 pg/ml, P<0.01) were elevated in CHF. LogIL-6 and logTNF-alpha were positively correlated (r=0.34 and r=0.35, respectively) with logplasma norepinephrine, and were negatively correlated (r=-0.39 and r=-0.32, respectively) with peak VO(2). Maximal exercise increased IL-6 and TNF-alpha both in controls and CHF (all P<0.01). Changes in IL-6 (DeltaIL-6) correlated with Deltaepinephrine (r=0.63, P<0.0001) and Deltanorepinephrine (r=0.57, P=0.0006) in controls, but not in CHF. DeltaTNF-alpha correlated with DeltaANP (r=0.28, P=0.01) only in CHF. In summary, cytokine activation at rest was associated with high plasma norepinephrine and exercise intolerance. Maximal exercise caused increases in IL-6 and TNF-alpha concentrations. Sympathetic activation seems to be important for the IL-6 increase during exercise in controls. In CHF, changes in ANP during exercise were associated with the exercise-induced increase in TNF-alpha, but still unknown mechanisms are involved for the cytokine activation during exercise.     

Augmented response in plasma brain natriuretic peptide to dynamic exercise in patients with left ventricular dysfunction and congestive heart failure

OBJECTIVES: We have previously demonstrated that patients with symptomatic congestive heart failure (CHF), but not with asymptomatic left ventricular dysfunction (LVD), have augmented plasma atrial natriuretic peptide (ANP) response to exercise. Plasma brain natriuretic peptide (BNP) response to exercise is less extensively studied. The aim of this study was to determine whether responses of plasma BNP during exercise normalized for exercise workload are altered in patients with LVD and CHF. SUBJECTS AND METHODS: Twenty-nine patients with LVD, 32 patients with CHF (NYHA classes II-III) and 27 age-matched control subjects were studied. Ventilatory, plasma ANP and BNP responses were assessed during symptom-limited cardiopulmonary exercise testing. Plasma natriuretic peptide levels were measured at rest and immediately after peak exercise. The increment in plasma BNP was divided by the increment in oxygen uptake (VO2) from rest to peak exercise, and this ratio [BNP exercise ratio: (peak BNP - rest BNP)/(peak VO2 - rest VO2)] was compared amongst the three groups. RESULTS: Peak VO2 (Control, LVD and CHF: 28.2 +/- 1.7, 21.1 +/- 1.8, 16.2 +/- 0.6 ml, min(-1) kg(-1), respectively), anaerobic threshold and peak workload became smaller as heart failure worsened. Resting and peak plasma ANP levels were significantly higher only in CHF, whilst resting and peak plasma BNP levels displayed a significant and continuous increase from normal subjects to LVD and CHF. The ANP exercise ratio (1.25 +/- 0.36, 2.61 +/- 0.57, 7.72 +/- 1.65, ANOVA P = 0.0002) was significantly higher only in patients with CHF, whilst the BNP exercise ratio (0.35 +/- 0.10, 2.60 +/- 0.69, 4.98 +/- 0.97, ANOVA P = 0.0001) was significantly higher in patients with LVD and became progressively higher in patients with CHF. CONCLUSIONS: These data showed that the BNP exercise ratio, an exercise plasma BNP response normalized with exercise workload, was augmented in patients with LVD, and became progressively higher in CHF, suggesting that an augmented exercise BNP ratio exists early in the course of developing CHF.     

Cardiopulmonary exercise test for evaluating cardiac reserve in chronic congestive heart failure]

To evaluate whether maximal oxygen consumption (VO2 max) measured by cardiopulmonary exercise test (CAR-PET) reflects cardiac reserve in patients with congestive heart failure (CHF), supine bicycle CAR-PET and exercise hemodynamic measurements were performed simultaneously in 12 patients with CHF of NYHA II-IV. With increasing workload, VO2 and cardiac output elevated gradually, then plateaued, demonstrating that patients with CHF could reach VO2max. According to VO2max, patients were divided into 4 classes: including 2 patients of class A (VO2max: 24.5 +/- 2.29 ml.min-1/kg, mean +/- s mean), 3 of B (17.6 +/- 1.37 ml.min-1/kg), 5 of C (13.6 +/- 0.66 ml.min-1/kg) and 2 of D (6.5 +/- 1.64 ml.min-1/kg). Maximal cardiac indices were 8.79 +/- 2.35 L.min-1/m2 in class A, 5.82 +/- 0.97 L.min-1/m2 in B, 3.53 +/- 0.95 L.min-1/m2 in C and 2.21 +/- 1.56 L.min-1/m2 in D. No significant correlation between supine resting hemodynamic parameters and VO2max/kg was found, suggesting that exercise tolerance could not be predicted by the measurement of resting cardiac performance. Furthermore, VO2max correlated poorly with NYHA classification in these patients. However, cardiac output correlated linearly with VO2 during exercise, suggesting that VO2 max/kg is a good predictor for cardiac reserve in CHF(CI = 0.6809 +/- 0.2748 VO2/kg, n = 40, r = 0.84, P < 0.0001; CO = 1.1618 +/- 7.9065 VO2, n = 40, r = 0.84, P < 0.0001). The results also showed that VO2max/kg did not correlate with the changes of pulmonary capillary wedge pressure (PCWP), indicating that exercise tolerance in CHF depends more on cardiac output than on ventilatory consequence of pulmonary congestion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prognostic value of time-related changes of cardiopulmonary exercise testing indices in stable chronic heart failure: a pragmatic and operative scheme.

BACKGROUND: Although peak oxygen consumption (VO2) is an objective measurement of functional capacity linked to survival, most clinicians use clinical history to monitor changes over time of functional disability. The aim was to verify the prognostic value of time-related changes (Delta) of symptom-limited cardiopulmonary exercise testing (CPX) indices in stable chronic heart failure (CHF). DESIGN AND METHODS: We studied 231 stable CHF patients (200 men) with left ventricular ejection fraction (LVEF) of 24 +/- 8% and peak VO2 of 14.3 +/- 8 ml/kg per min, who performed two symptom-limited CPX over time. RESULTS: The two incremental CPX were separated by a mean interval of 258 +/- 42 days; 59 (26%) suffered cardiovascular death or underwent urgent heart transplantation during the follow-up (1167 +/- 562 days). Peak VO2, LVEF (measured at second evaluation), Deltapeak VO2 and DeltaNYHA (New York Heart Association classification) were selected as independent predictors in the total population, and LVEF, Deltapeak VO2, and NYHA in patients with peak VO2 of 14 ml/kg per min or less (106 patients); no Delta parameter was selected in patients with preserved exercise tolerance. Survival analysis was performed taking into consideration the inter-test variability of peak VO2 (6%): true fall: more than 6% decrease, decline within the measurement variability; less than 6% decrease, improvement within the measurement variability; less than 6% increase and true rise; more than 6% increase: total mortality rate was 51, 23, 19 and 14% (P < 0.0001), respectively. CONCLUSIONS: Deltapeak VO2 is a useful outcome index; a combination of static (single) and time-related functional variables can enhance the prognostication process in stable CHF patients.     

Chronic heart failure in the very elderly: clinical status, survival, and prognostic factors in 188 patients more than 70 years old.

BACKGROUND: Chronic heart failure (CHF) is a frequent disease with a dismal prognosis, but little is known about survival in the very elderly. There are no data on the prognostic value of cardiopulmonary exercise testing in this population. We aimed to assess exercise capacity, survival, and prognostic parameters in elderly patients with CHF. METHODS: We evaluated 188 patients with CHF >70 years old (mean 77 +/- 4 years, range 70-94 years) seen at our heart failure clinic between March 1992 and June 1998. A cardiopulmonary exercise test was performed in 102 patients (peak VO2 15.3 +/- 4.7, VE/VCO2 slope 39.6 +/- 15.01). All patients were followed up for at least 12 months. The prognostic end point of the study was all-cause mortality. RESULTS: At the end of follow-up (16 +/- 10 mo, range 12-41 mo), 67 patients (35.6%) had died (1-year mortality rate 26% [95% confidence interval 20-32]). In univariate analysis New York Heart Association class (NYHA) (relative risk [RR] = 2.56, P <.0001), VE/VCO2 (RR = 1.041, P <.0001), peak VO2 (RR = 0.87, P =.0007), and fractional shortening (RR = 0.95, P <.0001) predicted mortality. Peak VO2 predicted mortality independently of age, NYHA class, and left ventricular ejection fraction. A subgroup of 12 patients with dynamic left ventricular outflow tract obstruction during stress had an excellent outcome, with a 100% survival at the end of follow-up (mean 16 +/- 7 mo, range 12-39 mo). CONCLUSIONS: The prognosis in elderly patients with CHF is poor. Valid exercise testing results can be obtained in more than 50% of elderly patients with CHF. NYHA class and peak VO2 are the strongest prognostic factors in this population.     

Rapid bedside measurement of brain natriuretic peptide in patients with chronic heart failure

BACKGROUND: Brain natriuretic peptide (BNP) levels have been used to assess clinical status and predict prognosis of patients with chronic heart failure (CHF). However, BNP levels can only be measured in specialized laboratories which has hampered its use in daily clinical practice. We compared a new, rapid, BNP assay with a conventional BNP measurement and evaluated the applicability to current practice by comparing it with standard clinical parameters. METHODS: BNP levels were determined in 78 stable CHF patients and 20 controls. The severity of CHF was assessed by determination of New York Heart Association functional class (NYHA), left ventricular ejection fraction (LVEF) and peak oxygen consumption (peak VO(2)), and these parameters were compared to BNP levels. RESULTS: Overall, rapid BNP assessment was highly correlated with the conventional BNP assay (r=0.95, P<0.0001). In the higher ranges (>200 pmol/l), however, correlation was less accurate, and tended to overestimate. BNP levels also strongly correlated with both NYHA class, LVEF and peak VO(2) (all P<0.001). A cut-off value for BNP of 20 pmol/l yielded a sensitivity of 91% and a specificity of 92% to detect the presence of left ventricular systolic dysfunction. CONCLUSIONS: Rapid measurement of BNP levels is comparable to conventional BNP measurement and strongly correlated to clinical tests that are currently used to stratify CHF patients. Wider use of this method may yield a reduction of costly and time-consuming clinical tests and may reduce the medical burden of CHF.     

Secretory sphingomyelinase is upregulated in chronic heart failure: a second messenger system of immune activation relates to body composition, muscular functional capacity, and peripheral blood flow.

AIMS: Sphingomyelinases (SMase) are key regulating enzymes of the intracellular and paracrine ceramide second messenger system that mediates immune response to inflammatory cytokines and oxidative stress. Vascular endothelial cells are a rich and regulatable source of secretory SMase (S-SMase). Chronic heart failure (CHF) is a state of endothelial dysfunction and latent immune activation. The significance of S-SMase has not been studied in CHF in detail. The aim of the present study is to characterize S-SMase activity in patients with CHF in relation to disease severity and to pathophysiological characteristics such as immune activation, vasodilator capacity, and skeletal muscle function and body composition. METHODS AND RESULTS: S-SMase activity was assessed by a fluorimetric method in 112 patients with CHF (age, 63 +/- 11 years; NYHA class I/II/III/IV, 9/48/46/9; LVEF, 30 +/- 15%; peak VO(2), 18.6 +/- 6.7 mL/kg/min) and in two control groups (healthy, n = 13 and hypertensive controls, n = 11). S-SMase activity was similar in both control groups (healthy, 150 +/- 121 pmol/mL h; hypertensive, 157 +/- 134 pmol/mL h) but was increased by >90% in CHF patients (299 +/- 283 pmol/mL h; P = 0.004). S-SMase elevation was not different between ischaemic and non-ischaemic CHF and increased stepwise with NYHA class (I, 206 +/- 202; II, 284 +/- 242; III, 306 +/- 212; IV, 440 +/- 665 pmol/mL h; P = 0.003). S-SMase correlated with peak VO(2) (R = -0.33, P = 0.0007) and with cytokine activation [tumour necrosis factor-alpha (TNF-alpha) R = 0.22, P = 0.02; sTNF-R1 R = 0.39, P < 0.0001]. S-SMase further correlated with reduced skeletal (quadriceps) muscle strength (R = -0.46, P < 0.0001) as well as impaired peripheral vasodilator capacity (R = -0.34, P = 0.02). In detailed body composition analysis (DEXA scan), S-SMase activity was highest in patients with cardiac cachexia (405 +/- 357 vs. non-cachectic patients: 233 +/- 202 pmol/mL h; P = 0.0007) and related to reduced lean tissue parameters but not to fat tissue parameters. In Cox proportional hazard analysis, elevated SMase related to impaired survival, independent of age, NYHA class, and mean BP (hazard ratio 2.92; 95% confidence interval 1.035-8.24; P = 0.04). CONCLUSION: S-SMase is upregulated in CHF, independent of aetiology. The association of S-SMase with clinical status, tissue amount, functional capacity of skeletal muscle tissue, and vasodilator capacity suggests that S-SMase-mediated signalling may contribute to regulatory processes of CHF pathophysiology.     

Combined endurance/resistance training reduces NT-proBNP levels in patients with chronic heart failure.

AIMS: This study was designed to evaluate the effects of combined endurance/resistance training on NT-proBNP levels in patients with chronic heart failure (CHF). The safety of resistive weight training for patients with CHF is questioned. Possible detrimental effects include an increase in ventricular diastolic pressure and secondary unfavourable remodelling. Circulating levels of the N-terminal fragment of brain natriuretic peptide (NT-proBNP) reflect left ventricular diastolic wall stress and are strongly related to mortality and treatment success in CHF. METHODS AND RESULTS: In this study, 27 consecutive patients with stable CHF and left ventricular ejection fraction (LVEF) <35% were enrolled in a 4 months non-randomized combined endurance/resistance training programme. Blood sampling for measurement of NT-proBNP, functional assessment, cardiopulmonary exercise testing, echocardiography and radionuclide angiography were performed at entry and after 4 months. After 4 months, exercise training caused a significant reduction in circulating concentrations of NT-proBNP (2124+/-397 pg/ml before, 1635+/-304 pg/ml after training, p=0.046, interaction), whereas no changes were observed in an untrained heart failure control group. NYHA functional class (p=0.02, interaction), maximal (peak VO2: p=0.035, interaction; maximal workload: p<0.00001, interaction) and submaximal (workload at anaerobic threshold: p=0.001, interaction; rate-pressure product at anaerobic threshold: p=0.001, interaction) exercise parameters as well as work efficiency (Wattmax/VO2peak: p=0.0001, interaction) were significantly improved. In addition, a decrease in left ventricular end-systolic diameter was observed in the trained heart failure group (p=0.016). CONCLUSION: Four months of combined endurance/resistance training significantly reduced circulating levels of NT-proBNP in patients with CHF, without evidence of adverse remodelling. Exercise training might offer additional non-pharmacological modulation of the activated neurohormonal pathways in the setting of CHF.     

Excessive ventilation during early phase of exercise: a new predictor of poor long-term outcome in patients with chronic heart failure

BACKGROUND: Studies demonstrating prognostic value of excessive exercise ventilation in chronic heart failure (CHF) have focused on data derived from the whole cardiopulmonary exercise test (CPET). Whether ventilatory response to early phase of exercise is useful for risk stratification in CHF is unknown. METHODS AND RESULTS: We evaluated 216 patients with systolic CHF who underwent CPET (age: 60+/-11 years, NYHA class [I/II/III/IV]: 18/104/77/17). Ventilatory response to exercise (slope of regression line relating ventilation to carbon dioxide production) was calculated from the whole exercise test (VE-VCO(2)-all) and from the first 3 min of exercise (early phase - VE-VCO(2)-3 min). During follow-up (mean: 40+/-20 months, >3 years in survivors), 89 (41%) CHF patients died. High VE-VCO(2)-all and VE-VCO(2)-3 min predicted poor outcome in single predictor analyses, and in multivariable models when adjusted for prognosticators (age, NYHA class, ejection fraction, peak VO(2)) (P<0.0001). In receiver operating characteristic curve analysis, areas under curve for 3-year follow-up were similar for VE-VCO(2)-all and VE-VCO(2)-3 min. VE-VCO(2)-3 min maintained its prognostic value in patients taking beta-blockers (P<0.0001) and those unable to perform maximal CPET (P=0.0009). CONCLUSIONS: In CHF patients, excessive ventilation assessed over the first 3 min predicts poor outcome. Assessment of ventilatory response to exercise for prognostic stratification may be extended to patients unable to perform maximal CPET.     

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.     

Neurohormonal determinants of peak oxygen uptake in patients with chronic heart failure

Chronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. This study determined whether peak oxygen uptake (VO2) can be predicted by the degree of neurohormonal and cytokine activations in CHF. Plasma norepinephrine. epinephrine, renin-angiotensin system activity, ANP, BNP, and serum interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha were measured in 84 CHF patients (age, 59 +/- 1 years, LVEF, 36 +/- 1%) and 34 controls. Maximal cardiopulmonary exercise testing was performed. Peak VO2 (Controls vs CHF: 27.8 +/- 1.3 vs 18.2 +/- 0.5 mL/min/kg, P < 0.0001) was lower in CHF. Patients with CHF had increased plasma norepinephrine (211 +/- 11 vs 315 +/- 24 pg/mL), renin activity (1.2 +/- 0.2 vs 6.2 +/- 1.1 ng/mL/hr), ANP (22 +/- 3 vs 72 +/- 7 pg/mL), and BNP levels (18 +/- 3 vs 200 +/- 25 pg/mL) (all P < 0.01). Serum IL-6 (1.1 0.1 vs 2.4 +/- 0.3 pg/mL) and TNF-alpha (2.7 +/- 0.2 vs 4.0 +/- 0.3 pg/mL) levels were higher in CHF (both P < 0.001). Univariate analysis revealed that age (P < 0.001), cardiothoracic ratio (P < 0.001), norepinephrine (P < 0.0001), ANP (P < 0.001), BNP (P < 0.01), and log IL-6 (P < 0.05) were significantly related with peak VO2. Stepwise regression analysis indicated that plasma norepinephrine and ANP emerged as significant determinants of peak VO2, independent of patient age (overall R = 0.61, P < 0.0001). In summary, patients with CHF exhibited activation of neurohormones and proinflammatory cytokines. Among the elevated hormonal and cytokine markers, plasma norepinephrine and ANP levels were independent predictors of exercise capacity.     

Dietary and blood antioxidants in patients with chronic heart failure. Insights into the potential importance of selenium in heart failure.

BACKGROUND: Chronic heart failure (CHF) seems to be associated with increased oxidative stress. However, the hypothesis that antioxidant nutrients may contribute to the clinical severity of the disease has never been investigated. AIMS: To examine whether antioxidant nutrients influence the exercise capacity and left ventricular function in patients with CHF. METHODS: Dietary intake and blood levels of major antioxidant nutrients were evaluated in 21 consecutive CHF patients and in healthy age- and sex-matched controls. Two indexes of the severity of CHF, peak exercise oxygen consumption (peak VO2) and left ventricular ejection fraction (LVEF), were measured and their relations with antioxidants were analysed. RESULTS: Whereas plasma alpha-tocopherol and retinol were in the normal range, vitamin C (P=0.005) and beta-carotene (P=0.01) were lower in CHF. However, there was no significant association between vitamins and either peak VO2 or LVEF. Dietary intake (P<0.05) and blood levels of selenium (P<0.0005) were lower in CHF. Peak VO2 (but not LVEF) was strongly correlated with blood selenium: r=0.76 by univariate analysis (polynomial regression) and r=0.87 (P<0.0005) after adjustment for age, sex and LVEF. CONCLUSIONS: Antioxidant defences are altered in patients with CHF. Selenium may play a role in the clinical severity of the disease, rather than in the degree of left ventricular dysfunction. Further studies are warranted to confirm the data in a large sample size and to investigate the mechanisms by which selenium and other antioxidant nutrients are involved in CHF.     

Effects of carvedilol on oxidative stress and chronotropic response to exercise in patients with chronic heart failure

BACKGROUND: Our previous studies suggest that the increase in heart rate from rest to peak exercise is reduced in patients with chronic heart failure (CHF) and this is associated with increased oxidative stress, as determined by malondialdehyde (MDA) plasma levels. AIM: To investigate the effects of carvedilol on the heart rate response to exercise and oxidative stress in patients with CHF. METHODS AND RESULTS: Thirty stable NYHA classes II-III CHF patients received carvedilol therapy for 6 months, at a mean maintenance dose of 25 mg (range 6.25-50 mg/day). After treatment, the patients showed a significant improvement in their functional NYHA class (p=0.013), increased left ventricular ejection fraction (LVEF) (24+/-1.4% to 31+/-2.3%, p=0.003) and 6-min walk distance (499+/-18 to 534+/-18 m, p=0.03), without changes in the peak VO2. At baseline, norepinephrine (NE) plasma levels increased with exercise (510+/-51 to 2513+/-230 pg/mL, p<0.001), and these levels were not affected by carvedilol. Chronotropic responsiveness index (increase in heart rate divided by the increase in NE from rest to peak exercise) was not changed by carvedilol (0.049+/-0.001 to 0.042+/-0.001, p=0.6). MDA levels of CHF patients decreased after treatment with carvedilol (2.4+/-0.2 to 1.1+/-0.2 microM, p<0.001), without changes in antioxidant enzyme activities. CONCLUSIONS: Carvedilol treatment in patients with CHF results in reduced oxidative stress without restoration of the chronotropic responsiveness index.     

Reduction in Circulating Testosterone Relates to Exercise Capacity in Men With Chronic Heart Failure

BackgroundWe investigated whether anabolic deficiency was linked to exercise intolerance in men with chronic heart failure (CHF). Anabolic hormones (testosterone, dehydroepiandrosterone sulfate, insulin-like growth factor 1 [IGF1]) contribute to exercise capacity in healthy men. This issue remains unclear in CHF.Methods and ResultsWe studied 205 men with CHF (age 60 ± 11 years, New York Heart Association [NYHA] Class I/II/III/IV: 37/95/65/8; LVEF [left ventricular ejection fraction]: 31 ± 8%). Exercise capacity was expressed as peak oxygen consumption (peak VO₂), peak O₂ pulse, and ventilatory response to exercise (VE-VCO₂ slope). In multivariable models, reduced peak VO₂ (and reduced peak O₂ pulse) was associated with diminished serum total testosterone (TT) (P < .01) and free testosterone (eFT; estimated from TT and sex hormone globulin levels) (P < .01), which was independent of NYHA Class, plasma N-terminal pro-brain natriuretic peptide, and age. These associations remained significant even after adjustment for an amount of leg lean tissue. In multivariable models, high VE-VCO₂ slope was related to reduced serum IGF1 (P < .05), advanced NYHA Class (P < .05), increased plasma NT-proBNP (P < .0001), and borderline low LVEF (P = .07). In 44 men, reassessed after 2.3 ± 0.4 years, a reduction in peak VO₂ (and peak O₂ pulse) was accompanied by a decrease in TT (P < .01) and eFT (P ≤ .01). Increase in VE-VCO₂ slope was related only to an increase in plasma NT-proBNP (P < .05).ConclusionsIn men with CHF, low circulating testosterone independently relates to exercise intolerance. The greater the reduction of serum TT in the course of disease, the more severe the progression of exercise intolerance. Whether testosterone supplementation would improve exercise capacity in hypogonadal men with CHF requires further studies.