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.     

Association of hyperadiponectinemia with severity of ventricular dysfunction in congestive heart failure.

BACKGROUND: Adiponectin, which is a collagen-like plasma protein produced by adipose tissue, has anti-atherogenic and anti-inflammatory effects. Plasma adiponectin levels in patients with congestive heart failure (CHF) were determined, as well as relationships between the plasma levels of adiponectin and other hormones. METHODS AND RESULTS: The study group comprised 90 patients with CHF and 20 control subjects, who were divided into 4 subgroups according to New York Heart Association (NYHA) functional class. Plasma levels of adiponectin, tumor necrosis factor (TNF)-alpha and brain natriuretic peptide (BNP) and cardiac hemodynamics were determined. Plasma adiponectin levels were significantly increased according to the severity of NYHA class in the patients with CHF; control: 6.2+/-1.0; NYHA I: 8.5+/-1.9, NYHA II: 12.0+/-2.2, NYHA III: 13.0+/-2.7, NYHA IV: 14.9+/-2.7 microg/ml (p=0.0008). Similarly, plasma BNP levels were significantly increased in accordance with the NYHA class. Plasma adiponectin levels correlated positively with BNP (r=0.40, p=0.0002) and TNF-alpha (r=0.49, p=0.0001), and correlated negatively with cardiac index (r=-0.27, p=0.05). In 24 of 46 patients in the NYHA III and IV subgroups, according to the prompt improvement in cardiac function, levels of both plasma adiponectin and BNP were significantly reduced (p<0.0001). CONCLUSION: Plasma adiponectin levels increased according to the severity of CHF and, moreover, they correlated with the plasma levels of BNP and TNF-alpha. These results indicate that augmented release of adiponectin is involved in the pathogenesis of CHF and further study is needed to elucidate its exact role.     

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.     

Serum adiponectin level as an independent predictor of mortality in patients with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) is associated with altered energy homeostasis and myocardial inflammation, hypertrophy, and fibrosis. Adiponectin, an insulin-sensitizing adipocytokine, may affect these pathogenic factors, and the circulating adiponectin level may serve as a biological marker of CHF. This study aimed to assess the significance of serum adiponectin as a prognostic marker for Japanese CHF patients. METHODS AND RESULTS: The serum adiponectin levels were compared between 54 (24 ischemic and 30 non-ischemic) CHF patients with left ventricular systolic dysfunction and 55 age- and gender-matched control subjects. The CHF patients also underwent simultaneous clinical assessment and measurements for brain natriuretic peptide (BNP) and parameters of lipid or glucose metabolism. Compared with the controls, the CHF patients showed significantly increased serum adiponectin levels [6.7 (4.9-12.6) vs 14.6 (9.7-25.4) microg/ml, p<0.0001]. In the CHF patients, the log-transformed values of the serum adiponectin levels positively correlated with the log-transformed values of the plasma BNP levels (p=0.0003, r=0.48) and inversely correlated with the body mass index (p=0.0006, r=-0.46). Furthermore, an increase in the serum adiponectin level was associated with higher mortality (p<0.05), particularly in the ischemic CHF patients (p<0.005). CONCLUSIONS: An increase in the circulating adiponectin level was associated with higher mortality in the ischemic CHF patients. Adiponectin may be an informative risk marker for Japanese CHF patients.     

Ongoing myocardial damage in chronic heart failure is related to activated tumor necrosis factor and Fas/Fas ligand system.

BACKGROUND: Elevated concentrations of cardiac troponin T and heart-type fatty acid-binding protein (H-FABP) identify patients with chronic heart failure (CHF) and ongoing myocardial damage (OMD) who are at increased risk for future cardiac events. Cardiomyocyte necrosis and/or apoptosis via activated tumor necrosis factor (TNF) and the Fas/Fas ligand (FasL) system may be related to the development of OMD. METHODS AND RESULTS: The serum concentrations of H-FABP, a sensitive marker of membrane damage of cardiomyocytes, soluble Fas (sFas) and TNF-alpha were measured in 38 patients with CHF. The concentrations of H-FABP, TNF-alpha and s-Fas in patients with New York Heart Association (NYHA) III + IV were all significantly higher than in those patients in NYHA II (H-FABP; III + IV 9.3+/-5.9 vs II 5.1+/-1.8 ng/ml, p=0.003, TNF-alpha; III + IV 10.5+/-3.8 vs II 8.0+/-2.7 pg/ml, p=0.02, sFas; III + IV 3.36+/-1.37 vs II 2.58 +/-0.84 ng/ml, p=0.03). Increased concentrations of H-FABP significantly correlated with the concentrations of TNF- alpha (r=0.57, p=0.0001) and sFas (r=0.69, p<0.0001), independent of renal function. CONCLUSION: OMD detected by H-FABP, a marker of membrane damage, is related to activated TNF and the Fas/FasL system, which suggests a pathophysiological role of cardiomyocyte necrosis and/or apoptosis in patients with worsening heart failure.     

The anti-CD14 antibody IC14 suppresses ex vivo endotoxin stimulated tumor necrosis factor-alpha in patients with chronic heart failure

BACKGROUND: Activation of the endotoxin (LPS) receptor, CD14, leads to tumor necrosis factor-alpha (TNF) production. Plasma LPS activity is elevated in patients with severe chronic heart failure (CHF). An anti-CD14 antibody, IC14, blocks TNF production in healthy volunteers. It is not known whether IC14 prevents TNF production in CHF patients. METHODS AND RESULTS: Blood from 20 CHF patients (age 64+/-2.1 years, NYHA class 2.2+/-0.1, LVEF 27+/-3%, mean+/-SEM) was pre-incubated with 0.5, 1.0, 5.0, 10 and 50 microg/mL IC14 for 1 h followed by incubation with 1 or 10 ng/mL LPS for 6 h. Fourteen subjects served as controls (58+/-2.4 years). LPS-stimulated TNF release was 76% and 60% greater at 1 and 10 ng/mL LPS, respectively, in CHF patients versus controls (p=0.07 and p=0.008). IC14 at concentrations of 5.0, 10 and 50 microg/mL substantially reduced TNF production in response to stimulation with LPS (all p<0.05). CD14 receptor density was similar in patients and controls. In controls, but not in CHF patients, there was a positive correlation between CD14 receptor density and TNF production (r=0.61, p=0.03). CONCLUSION: IC14 suppresses LPS-stimulated whole blood TNF production in patients with CHF and in normal subjects and therefore may represent a novel therapeutic strategy for CHF patients with systemic immune activation.     

Chronic heart failure. The relationship between increased activity of skeletal muscle ergoreceptors and reduced exercise tolerance

BACKGROUND: In chronic heart failure (CHF), skeletal muscle abnormalities may lead to the overactivation of ergoreceptors which in turn may cause sympathetic overactivation and increased ventilatory response to exercise. AIM: To assess ergoreceptor reflex response to exercise and to evaluate whether ergoreceptor overactivity is related to the progression of CHF. METHODS: In 69 patients with CHF (66 males, mean age 62.7+/-11.6 years, NYHA class I/II/III/IV - 11/32/24/2 patients, respectively) and 24 controls without CHF (22 males, mean age 59+/-4.6 years) the ergoreflex contribution to the ventilatory and haemodynamic responses to exercise was evaluated. Moreover, in 13 patients with CHF, reproducibility of the measurements was assessed by repeating the test 1 to 7 days later. RESULTS: Enhanced ergoreflex effects on ventilation (1.9+/-1.6 vs 0.14+/-0.7 l/min, p<0.05) and systolic blood pressure (19.2+/-14.9 vs 6.1+/-5.9 mmHg, p<0.05) were found in patients with CHF compared with control subjects. Ergoreceptor overactivity was associated with a worse symptomatic state (NYHA class I vs II vs III, IV: 0.9 vs 1.5 vs 2.9 l/min, p<0.05) and lower exercise tolerance (peak V0(2): r=-0.51, p<0.0001; VE/VC0(2): r=0.50, p<0.0001). The mean values of the ergoreceptor reflex did not differ significantly between the two tests (t=1.5, p=0.14; variability coefficient = 21.5%). CONCLUSIONS: In CHF, overactivation of the ergoreflex is associated with the progression of the syndrome and may be responsible for reduced exercise tolerance. Reproducibility of ergoreflex measurements is satisfactory.     

Elevated circulating levels of thioredoxin and stress in chronic heart failure

BACKGROUND: Chronic heart failure (CHF) is a complex syndrome, in which reactive oxygen species and inflammatory cytokines are important stressors that contribute to the pathogenesis. AIM: We have studied physiological stress response parameters in CHF, in particular the redox-active regulator thioredoxin. SUBJECTS: A case-control study was conducted including a consecutive sample of CHF patients (n=27) of NYHA class II and III; comparison control subjects (n=29) were recruited from an association for retired people. METHOD: Baseline levels of Trx, lipid peroxides (oxidative stress), TNF and IL-6 cytokines, platelet-activation marker P-selectin, cortisol (as peripheral effector of HPA axis), and the potent antioxidant selenoprotein Trx-reductase were assessed. RESULTS: Mean (+/-S.E.M.) plasma levels of Trx were significantly higher in patients with CHF (32+/-3 ng/ml), than in the healthy subjects (12+/-3 ng/ml, P<0.0001). Trx levels increased in proportion to severity of disease (NYHA class III>NYHA class II) and degree of stress. Trx elevation correlated well with increased oxidative stress (lipid peroxides, P<0.0001), circulatory P-selectin (P<0.0001), morning level of free salivary cortisol (P=0.0002), and serum creatinine (P=0.0417), but not with pro-inflammatory cytokines TNF and IL-6. CONCLUSION: Trx was strikingly elevated in heart failure cases compared with controls, signifying an adaptive stress response that is higher the more severe the disease.     

Differences between cardiologists and internists in the management of heart failure. Medical guidelines compared with every-day practice

BACKGROUND: A marked progress in the treatment of chronic heart failure (CHF) took place during the last decade. Large, randomised studies documented the role of angiotensin-converting enzyme inhibitors (ACE-I) and beta-blockers in the reduction of mortality and morbidity in CHF. AIM: To assess differences in the management of CHF patients between cardiologists and internists. METHODS: Medical records of 433 patients with CHF, aged 38-98 years, hospitalised between October 2000 and May 2002 in an academic centre, were retrospectively analysed. Cardiologists treated 241 patients, and internists - 192 patients. In addition, 12 randomly selected physicians who treated CHF patients, filled-in a questionnaire concerning CHF treatment. Next, the answers were compared with the actual treatment, documented in patients medical files. RESULTS: There were significant differences in the CHF treatment between cardiologists and internists. Cardiologists significantly more often prescribed ACE-I in NYHA class III patients (77% vs 58%, p=0.003), beta-blockers in all NYHA classes (80% vs 57%, p<0.001), loop diuretics in NYHA classes III and IV (76% vs 42%, p<0.001 and 91% vs 44%, p=0.005), and thiazides in NYHA class III patients (36% vs 11%, p<0.001). Internists more often used loop diuretics (37% vs 15%, p<0.001), digoxin (28% vs 7%, p<0.001) and aldosterone antagonists (24% vs 13%, p=0.022) in NYHA class II patients. All cardiologists and almost half of internists declared combined usage of ACE-I and beta-blockers at increasing dosages as the treatment was continued. The highest concordance between declared and actual medication concerned the concomitant use of ACE-I and beta-blockers. CONCLUSIONS: Cardiologists used more often ACE-I and beta-blockers than internists in the treatment of CHF patients. A satisfactory knowledge of treatment guidelines was not associated with widespread usage of ACE-I and beta-blockers in every-day practice.     

Proinflammatory cytokine activation is linked to apoptotic mediator, soluble Fas level in patients with chronic heart failure

The Fas/Fas Ligand system is a major apoptosis signaling pathway that is up-regulated in patients with chronic heart failure (CHF). Serum soluble Fas (sFas) levels increase in proportion to the CHF severity and may have prognostic value, therefore, sFas is a promising biomarker of heart failure. In this study, we attempted to identify the determinants of sFas levels in patients with CHF. Serum levels of tumor necrosis factor (TNF)-α and its soluble receptors (sTNF-R1 & sTNF-R2), interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), glycoprotein (gp)130, and sFas were measured in 106 patients with CHF and 39 controls. All subjects performed a symptom-limited cycle ergometer exercise test with expired gas analysis. CHF patients had higher levels of TNF-α, sTNF-R1, sTNF-R2, IL-6, and gp130. Serum levels of sFas (controls versus CHF; 2.60 ± 0.88 versus 3.38 ± 1.23 ng/mL, P = 0.0004) were higher in CHF. On univariate analysis, age (P = 0.0003), NYHA functional class (P = 0.0012), peak VO2 (P < 0.0001), plasma norepinephrine (P = 0.0013), log IL-6 (P < 0.0001), log TNF-α (P = 0.0002), log sTNF-R1 (P < 0.0001), and log TNF-R2 (P < 0.0001) were significantly related to log sFas levels. Multivariate analysis showed that age and log IL-6 and log sTNF-R1 levels were independently associated with log sFas levels (overall R = 0.603, P < 0.0001). Serum levels of sFas were increased in patients with CHF, and age and serum IL-6 and sTNF-R1 levels were independent determinants of sFas levels. These data suggest that proinflammatory cytokine activation is linked to the Fas/Fas Ligand system in patients with CHF.     

Heart rate variability in heart failure

BACKGROUND: Heart rate variability (HRV) depicts the functional status of the autonomic nervous system and its effects on sinus node. Recently, HRV analysis has been introduced in patients with heart failure (CHF) to identify those who are at risk of cardiac death. AIM: To analyse HRV in patients with CHF with depressed left ventricular ejection fraction (EF) and to relate HRV parameters to EF, NYHA functional class and other clinical parameters. METHODS: The study group consisted of 105 patients with CHF (88 males, 17 females, mean age 54+/-12 years); 77 patients had ischaemic cardiomyopathy, and 28 - dilated cardiomyopathy. All patients were in NYHA class II-IV and had EF <40%. The mean value of echocardiographically assessed EF was 26.9+/-8.3%. The control group consisted of 30 gender- and age-matched healthy subjects. HRV analysis was performed in the time-domain from 24-hour Holter ECG. RESULTS: All HRV variables were significantly lower in patients with CHF than in controls. Patients with NYHA class II had higher values of SDNN and SDANN than those in class III or IV. Patients with sustained or non-sustained ventricular tachycardia (VT) detected during Holter monitoring had lower SDNN and SDANN values than those without VT. Patients with diabetes had significantly lower SDNN and rMSSD values than the patients without diabetes. Similar results were found when patients with or without hypertension were compared. HRV parameters were similar in patients either with ischaemic or dilated cardiomyopathy. Also the values of EF were similar (27.4+/-8.4 vs 25.0+/-8.3%, respectively, NS). In the whole group of patients with CHF the values of SDNN and SDANN significantly correlated with EF (SDNN p<0.001, r=0.42; SDANN p<0.001, r=0.51). This correlation was stronger in the subset of patients with ischaemic cardiomyopathy (SDNN p=0.002. r=0.54; SDANN p=0.002; r=0.53) than in those with dilated cardiomyopathy (SDNN p=0.012, r=0.23; SDANN p=0.008, r=0.42). A significant negative correlation was found between all HRV parameters and NYHA class (SDNN p<0.001, r = -0.33; SDANN p<0.001, r = -0.38; rMSSD p<0.001, r = -0.13). CONCLUSIONS: HRV is depressed in patients with CHF compared with healthy subjects. Among patients with CHF, HRV is further decreased in patients with more advanced NYHA class, lower EF and in those with diabetes, hypertension or VT on Holter monitoring.     

Beneficial effects of Waon therapy on patients with chronic heart failure: results of a prospective multicenter study

BACKGROUND: We conducted a prospective multicenter case-control study to confirm the clinical efficacy and safety of Waon therapy on chronic heart failure (CHF). METHODS: Patients (n=188) with CHF were treated with standard therapy for at least 1 week, and then were randomized to Waon therapy (n=112) or a control group (n=76). All patients continued conventional treatment for an additional 2 weeks. The Waon therapy group was treated daily with a far infrared-ray dry sauna at 60 degrees C for 15min and then kept on bed rest with a blanket for 30min for 2 weeks. Chest radiography, echocardiography, and plasma levels of brain natriuretic peptide (BNP) were measured before and 2 weeks after treatment. RESULTS: NYHA functional class significantly decreased after 2 weeks of treatment in both groups. Chest radiography also showed a significant decrease of the cardiothoracic ratio in both groups (Waon therapy: 57.2+/-8.0% to 55.2+/-8.0%, p<0.0001; control: 57.0+/-7.7% to 56.0+/-7.1%, p<0.05). Echocardiography demonstrated that left ventricular diastolic dimension (LVDd), left atrial dimension (LAD), and ejection fraction (EF) significantly improved in the Waon therapy group (LVDd: 60.6+/-7.6 to 59.1+/-8.4mm, p<0.0001; LAD: 45.4+/-9.3mm to 44.1+/-9.4mm, p<0.05; EF: 31.6+/-10.4% to 34.6+/-10.6%, p<0.0001), but not in the control group (LVDd: 58.4+/-10.3mm to 57.9+/-10.4mm; LAD: 46.3+/-9.7mm to 46.2+/-10.1mm; EF: 36.6+/-14.1% to 37.3+/-14.0%). The plasma concentration of BNP significantly decreased with Waon therapy, but not in the control group (Waon: 542+/-508pg/ml to 394+/-410pg/ml, p<0.001; control: 440+/-377pg/ml to 358+/-382pg/ml). CONCLUSION: Waon therapy is safe, improves clinical symptoms and cardiac function, and decreases cardiac size in CHF patients. Waon therapy is an innovative and promising therapy for patients with CHF.     

Soluble TNF-alpha and interleukin-6 receptors in the urine of heart failure patients. Their clinical value and relationship with plasma levels

BACKGROUND: Proinflammatory cytokines are important mediators in heart failure (HF). Recently, urinary levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have been determined. AIMS: The purpose of this study was to measure the urinary levels of TNF-alpha and IL-6 receptors, sTNF-RI, sTNF-RII, sIL-6R, and the relationship with plasma levels and NYHA classes in HF. METHODS: Plasma and urine were collected from 114 HF patients and sTNF-RI, sTNF-RII and sIL-6R (ng/ml) were analyzed. RESULTS: For the whole population, plasma levels of sTNF-RI were 2.1+/-0.1, of sTNF-RII were 5.0+/-0.3 and of sIL-6R were 49.8+/-2.5. Urinary levels were: sTNF-RI, 2.8+/-0.5, r=0.5, p<0.001; sTNF-RII, 12.6+/-2.1, r=0.4, p<0.001; and sIL-6R, 4.2+/-0.4, NS. In NYHA III subjects, we found sTNF-RI, r=0.6, p<0.01, sTNF-RII, r=0.5, p<0.05, and sILR-6, r=0.5, p<0.05. Both plasma TNF receptors and urinary levels of sTNF-RII were higher in patients in a more severe NYHA class (p<0.05). CONCLUSIONS: Urine is a good environment to study sTNF-RI and sTNF-RII, and this fact has diagnostic and prognostic implications. Plasma and urinary levels of TNF receptors showed a fair correlation, which was increased in higher NYHA classes. Plasma and urinary levels of sIL6R showed a good correlation in NYHA III. The TNF receptor levels in urine increased in patients with more severe HF.     

Cardiac troponin T vs other biochemical markers in patients with congestive heart failure.

BACKGROUND: Several pathologic processes can cause myocardial injury, which is followed by cardiac remodeling and congestive heart failure (CHF). Cardiac troponin T (cTnT), a specific and sensitive marker of myocardial injury, has been related to long-term outcome in patients with CHF, so the relationship between cTnT and other biochemical markers associated with the pathophysiology of CHF was investigated in the present study. METHODS AND RESULTS: Between February 2004 and December 2005, 145 consecutive hospitalized patients (mean left ventricular ejection fraction (LVEF) 31.6+/-0.9%) with CHF were divided into low (<0.01 ng/ml) and high (> or =0.01 ng/ml) serum cTnT groups. Correlations with other prognostic biochemical markers, including brain natriuretic peptide (BNP), type I collagen C-terminal telopeptide (ICTP), procollagen type III peptide (PIIIP), renin, norepinephrine (NOREPI), C-reactive protein (CRP), cholesterol, hemoglobin (Hb), uric acid and HbA1c were examined. cTnT was high in 46 (32%) and low in 99 (68%) patients at baseline. Patients with high cTnT had abnormally high blood concentrations of BNP (p<0.0001), ICTP (p<0.0001), PIIIP (p=0.0006), NOREPI (p=0.0119), CRP (p=0.0003), uric acid (p=0.0026) and HbA1c (p=0.0361). In contrast, concentrations of cholesterol and Hb were significantly lower in patients with high cTnT (p=0.0319 and 0.0005, respectively). Death from or rehospitalization for CHF occurred in 41% in the high vs 9% in the low cTnT group (p=0.0002). Univariate analysis showed that high cTnT (p=0.0005), BNP (p=0.0001), renin (p=0.0158), NOREPI (p=0.0094), old age (p=0.0390), low LVEF (p=0.0231) and high New York Heart Association (NYHA) class (p=0.0006) were predictors of death from or rehospitalization for CHF. By multivariate analysis including BNP, NOREPI, age, LVEF and NYHA class, high cTnT and renin remained as significant predictors. CONCLUSIONS: Patients with ongoing myocardial injury and high cTnT had associated findings consistent with activation of the sympathetic system, synthesis of cardiac fibrosis, inflammation and metabolic abnormalities. By multivariate analysis, high cTnT and renin remained significant predictors of death or rehospitalization.     

Skeletal muscle mass independently predicts peak oxygen consumption and ventilatory response during exercise in noncachectic patients with chronic heart failure

OBJECTIVES: We sought to assess whether skeletal muscle mass might be a predictor of peak oxygen consumption (Vo2) and relation of the ventilation to carbon dioxide production (VE/VCo2) slope in patients with chronic heart failure (CHF) independent of clinical conditions, neurohormonal activation and resting hemodynamics. BACKGROUND: A variety of abnormalities characterize skeletal muscle and contribute to exercise intolerance in patients with CHF. Skeletal muscle mass is a determinant of peak Vo2 both in healthy patients and in patients with CHF, but there are no reports on the independent predictive value of this parameter, which can be measured with great accuracy by whole-body dual energy X-ray absorptiometry (DEXA). The influence of skeletal muscle mass on VE/VCo2 slope is not known either. METHODS: We prospectively evaluated 120 consecutive noncachectic patients with CHF. Every patient underwent a cardiopulmonary exercise test, an echo-Doppler examination and an evaluation of neurohormonal activation and body composition as assessed by DEXA. RESULTS: At the univariate analysis, New York Heart Association (NYHA) class (p < 0.0001), age (p < 0.0001), male gender (p < 0.0001) and plasma renin (p < 0.0001) significantly related with peak Vo2. There was a significant correlation between lean mass and absolute peak Vo2 (r = 0.70, p < 0.0001) and VE/VCo2 slope (r = -0.27; p < 0.01). At the multivariate analysis, lean mass predicted peak Vo2 and VE/VCo2 slope independently of NYHA functional class, age, gender, neurohormonal activation and resting hemodynamics. CONCLUSIONS: Skeletal muscle mass is an independent predictor of peak Vo2 and VE/VCo2 slope in stable noncachectic patients with CHF. Future studies will determine whether an increase in skeletal muscle mass in the individual patient might result in an improvement in parameters of exercise capacity.     

Plasma concentration of atrial natriuretic peptide is related to the duration of atrial fibrillation in patients with advanced heart failure

BACKGROUND: Plasma concentration of atrial natriuretic peptide (ANP) is elevated in patients with atrial fibrillation (AF) and in patients with chronic heart failure (CHF).Aim. To assess ANP level in patients with permanent AF and advanced CHF. METHODS: The study group consisted of 41 patients (27 males, mean age 62+/-8 years) with AF of a mean duration of 8.8 months. Twenty six (63%) patients were in NYHA class II, and 15 (37%) - in NYHA class III or IV. All patients underwent clinical and echocardiographic evaluation as well as ANP plasma concentration assessment. Multiple regression analysis was used to identify factors which determine ANP plasma concentration. RESULTS: Mean ANP plasma concentration was 52.4+/-22.7 pg/ml in the whole study group; 38.6+/-10.8 pg/ml in NYHA class II patients and 74.9+/-18.7 pg/ml in NYHA class III-IV subjects (p<0.0001). Among echocardiographic parameters, patients with NYHA class III or IV had significantly lower left ventricular ejection fraction and greater left atrial volume than patients with NYHA class II (32% versus 56%, p<0.0001 and 101.0+/-23.8 cm(3) versus 83.4+/-16.1 cm(3), p<0.006, respectively). Multiple regression analysis revealed a significant negative correlation between AF duration and ANP level (p=0.0013) in a group of patients with NYHA class III or IV and identified AF duration as an independent predictor of ANP plasma concentration in this group of patients. CONCLUSIONS: ANP plasma concentration in patients with persistent AF and advanced CHF is determined by AF duration - the longer the AF duration the lower the ANP level.     

Response of the oxygen uptake efficiency slope to exercise training in patients with chronic heart failure

BACKGROUND: The oxygen uptake efficiency slope (OUES) is a new exercise parameter that provides prognostic power in patients with CHF. Little is known about the effects of exercise training (ET) on OUES. AIM: To describe the response of OUES to 6 months of ET in CHF patients and compare its evolution to that of other exercise variables. METHODS: 35 patients with CHF (NYHA II-III, age 54+/-9y, LVEF 31+/-10%) performed 3 maximal exercise tests, i.e. at the start, middle and end of a 6 month ET program. OUES, PeakVO(2), ventilatory anaerobic threshold (VAT) and slope VE/VCO(2) were determined. RESULTS: OUES, peakVO(2), VAT, slope VE/VCO(2), peak Watt, 6MWT and NYHA-class improved during the first part of the ET period (p<0.05). Only VAT, peak Watt and 6MWT continued to improve during the second part of the ET period (p<0.05) Improvements in OUES correlated better with improvements in peakVO(2) (r=0.77, p<0.001), than changes in other prognostic variables. DISCUSSION: OUES improves significantly after 6 months of ET. Changes in peakVO(2) correlate best with changes in OUES. OUES is sensitive to ET and can be used to evaluate the progression of exercise capacity in CHF patients.     

Impact of oxidative stress on plasma adiponectin in patients with chronic heart failure

BACKGROUND: Adiponectin, which is an adipocyte-specific cytokine that has a beneficial effect in cardiovascular disease, may be downregulated by oxidative stress in patients with chronic heart failure (CHF). Plasma levels of both adiponectin and biomarkers of oxidative stress are increased and have a prognostic impact on CHF patients. METHODS AND RESULTS: The plasma adiponectin level was measured in 116 patients with CHF (left ventricular ejection fraction <45%) who underwent cardiac catheterization, and these findings were compared with the atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) levels, hemodynamic parameters and plasma oxidized low-density lipoprotein (oxLDL) level as a marker of oxidative stress. There was no correlation between the plasma adiponectin level and hemodynamic parameters, but there was a positive correlation with the cardiac natriuretic peptides [ANP (r(s)=0.464, p<0.0001) or BNP (r(s)=0.489, p<0.0001)]. There was a significant negative correlation between plasma adiponectin level and oxLDL (r=-0.245, p=0.0079). In the stepwise multivariate analysis, a high level of natriuretic peptide (log BNP) (p=0.0098), and a low level of oxLDL (p=0.0105) were independent predictors of a high adiponectin level in CHF patients. CONCLUSIONS: The plasma adiponectin level is regulated not only by cardiac natriuretic peptides but also by oxidative stress in patients with CHF.     

Exercise skeletal muscle blood flow is related to peripheral microvascular stiffness in idiopathic dilated cardiomyopathy.

Peripheral microvascular function plays an important role in congestive heart failure (CHF). Decreased exercise blood flow and microvascular dysfunction have been described in CHF and both factors are regarded as parameters that might influence exercise capacity in these patients. Whether these factors are related to or can be characterized in clinical severity of CHF has not been elucidated in this population. Skeletal muscle blood flow (SMBF) was measured continuously noninvasively, by means of the local isotope washout technique using (133)Xenon, in musculus tibialis anterior during graded maximal supine bicycle exercise. The distensibility in skeletal muscle was measured in a papaverine-relaxed vascular bed using (99m)Tc-pertechnetate. The investigation included 20 patients with moderate CHF (NYHA II), 11 patients with severe CHF (NYHA III, IV) due to idiopathic dilated cardiomyopathy (IDCM), and 31 age-matched healthy subjects. The maximal SMBF level was significantly lower in severe CHF (3.6 +/- 2.5 (ml x (100 g x min)(-1))) compared with moderate CHF (8.6 +/- 5.1 (ml x (100 g x min)(-1)); P < 0.005) and controls (11.0 +/- 4.1 (ml x (100 g x min)(-1)); P < 0.0001), but similar between moderate CHF and controls. Distensibility in skeletal muscle was decreased in severe CHF (12 +/- 8%) compared with controls (44 +/- 17%; P < 0.0001 vs severe CHF) and decreased with increasing severity of CHF (moderate CHF, 23 +/- 14%; P < 0.0005 vs controls). In CHF patients, a relationship was demonstrated between skeletal muscle distensibility and the maximal SMBF (P < 0.0001; r = 0.70). Moreover, maximal SMBF correlated directly to exercise time (P < 0.005; r = 0.54). Patients with CHF have reduced exercise SMBF, which may be a limiting factor for the reduced maximal exercise capacity. Moreover, microvascular distensibility in skeletal muscle is reduced and correlates to maximal exercise SMBF. Furthermore, maximal SMBF correlates to exercise time. This implies that increased skeletal muscle microvascular stiffness may contribute to the reduced blood flow during exercise and SMBF may partly limit exercise performance in CHF patients due to IDCM.     

The significance of CA125 levels in patients with chronic congestive heart failure. Correlation with clinical and echocardiographic parameters

OBJECTIVE: To assess serum levels of carbohydrate antigen 125 (CA125) in patients with chronic congestive heart failure (CHF) and to assess any correlation with clinical symptoms and echocardiographic indices. PATIENTS AND METHODS: We enrolled 77 male patients (mean age: 73+/-10 years) admitted to the Cardiology Emergency Department (ED) with cardiac symptoms requiring hospitalization. Diagnosis of CHF was based upon medical history or initial echocardiographic evaluation on current admission. Serum CA125 was measured by an enzyme immunoradiometric assay, on admission and before discharge. RESULTS: The median overall CA125 value was 22.4 (11.5-48.9) U/ml. Serum CA125 levels were related to the severity of CHF [New York Heart Association (NYHA) class I: 19.2 (7.2-31) U/ml, NYHA class II: 17.6 (10-23) U/ml, NYHA class III: 32 (25-77) U/ml and NYHA class IV: 34.3 (18.6-77) U/ml (p<0.04)]. Patients in NYHA classes III and IV had significantly higher mean values of CA125, than patients in class II (p<0.005 and p<0.05, respectively). Moreover, patients with fluid congestion (pulmonary congestion, ankle edema) had higher levels of serum CA125 than patients without congestion (p=0.002 and p<0.03, respectively). Finally, levels of serum CA125 correlated weakly with right ventricular systolic pressure (RVSP) and renal function, while no significant correlation was found between CA125 and E wave deceleration time on Doppler echocardiography, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), liver function and the medical treatment prescribed. CONCLUSION: Serum CA125 is associated with the clinical severity of CHF and the symptoms and signs of fluid congestion and therefore may be a useful additional tool for the evaluation and clinical staging of these patients.