Moderate Chronic Heart Failure Research Articles

Abstract 12770: Left-Atrial Contractile Contribution to Left Ventricle Filling is Preserved in Moderate Chronic Heart Failure

Introduction: The extent that left atrium (LA) functional remodeling is impacted by left ventricle (LV) systolic function or clinical history in patients with chronic heart failure (HF) is unresolved. Cardiac imaging and plasma biomarkers may provide valuable information in this regard. Hypothesis: Elastic and active contributions to LV stroke volume (LV SV) are variable, independent of LV systolic function and reflected in natriuretic peptide measurements. Methods: We recruited 27 controls without overt cardiovascular disease and 68 patients with moderate HF, including preserved and reduced LV ejection fraction (LVEF). Cardiac MRI was used to evaluate LV volumes at end diastole and end systole, and LA volumes at end diastole, diastasis and end systole to determine passive and active volume changes. Plasma mid-region pro-atrial and N-terminal pro-brain natriuretic peptides (MR-proANP and NT-proBNP, respectively) were measured. Results: Elastic LA contribution to LV SV was significantly lower in HF (median, IQR: 14%, 8-23%) than controls (24%, 17-30%; p=0.001), but active contribution was not (23%, 0-34% vs 24%, 21-31%; p=0.163). In patients with HF, active LA contribution to LV SV was negatively associated with history of hypertension (β=-0.41, p=0.007) and positively associated with aging (β=0.40, p=0.008) in a multiple linear regression model. Seven of nine subjects with HF and a history of atrial fibrillation (AF), but in sinus rhythm (SR) on the day of study, had active LA contributions to LV SV >15%. Increased LA volume at end diastole (β=0.51, p=0.001) and LVEF (β=-0.33, p=0.008) were independently associated with NT-proBNP (β=0.51, p=0.001) in a model that included age and history of AF. Similarly, LA volume at end diastole (β=0.48, p=0.001) was independently associated with MR-proANP in a model that included age and history of AF. Notably, natriuretic propeptides were not associated with elastic or active LA contributions to LV SV. Conclusions: Heart failure is characterized by preserved LA active contribution to LV SV, regardless of LVEF, which increases with age, and is modifiable by hypertension and AF. Imaging-based assessment can elucidate the contribution of LA function in HF and may provide insight into the impact of AF in patients with HF.

Abstract 302: Sex Differences In Nonlinear Dynamics And Their Circadian Variation In Control Dogs And In A New Arrhythmogenic Canine Model Of Heart Failure

Introduction: Females can be more arrhythmogenic than males, and this sex difference can persist with development of chronic heart failure (CHF). The aim of this study was to investigate sex differences in the arrhythmogenic substrate in control dogs and in a new arrhythmogenic canine model of CHF. Methods: CHF was induced in 30 dogs by aortic insufficiency and aortic constriction. Holter monitoring assessed VT and PVCs from 30 dogs, as well as traditional HRV measures and nonlinear dynamics (including correlation dimension (CD), detrended fluctuations analysis α1 (DFAα1), and Shannon entropy (SE)) at baseline, 240 days (240d) and 720 days (720d) after CHF induction. Results: At baseline, females had lower LF/HF (0.27±0.03 vs 0.33±0.02, p=0.04), CD (1.60±0.17 vs 2.21±0.15, p=0.01), DFAα1 (0.62±0.03 vs 0.72±0.03, p=0.03), and SE (2.99±0.02 vs 3.10±0.03, p=0.03 vs males). Females lacked circadian variation in LF/HF, DFAα1, and SE while males had circadian variation in all of these. Of 11 dogs with frequent runs of VT and PVCs, 95% and 91% of total VT runs and total PVCs, respectively, were in females. With CHF, all these linear and nonlinear parameters progressively declined in males and females. CHF females had less decline in LF/HF than males so that by 720 days there was no more sex difference (0.24±0.06, 0.17±0.03 in females vs 0.22±0.05, 0.18±0.01 in males at 240d, 720d). However, for nonlinear parameters of CD, DFAα1, and SE, CHF females had lower values than males (CD: 1.56±0.21, 0.99±0.32 vs 1.87±0.24, 1.50±0.34; DFAα1: 0.51±0.05, 0.43±0.04 vs 0.54±0.07, 0.48±0.04; and SE 2.93±0.08, 2.76±0.08 vs 3.01±0.11, 2.91±0.04 in females vs males at 240d, 720d). With CHF, circadian variation in CD, DFAα1, and SE were lost in both males and females. Conclusions: There are sex differences in the arrhythmogenic substrate in control dogs and in this new arrhythmogenic canine model of moderate CHF. At baseline, females have lower sympathetic stimulation, reduced cardiac chaos, and loss of circadian variation in nonlinear dynamics. With CHF, sex differences in nonlinear dynamics persist; this reflects a loss of complexity and fractal properties that could contribute to increased arrhythmias in female CHF dogs.

Combined aerobic/inspiratory muscle training vs. aerobic training in patients with chronic heart failure

Vent-HeFT is a multicentre randomized trial designed to investigate the potential additive benefits of inspiratory muscle training (IMT) on aerobic training (AT) in patients with chronic heart failure (CHF). Forty-three CHF patients with a mean age of 58 ± 12 years, peak oxygen consumption (peak VO2 ) 17.9 ± 5 mL/kg/min, and LVEF 29.5 ± 5% were randomized to an AT/IMT group (n = 21) or to an AT/SHAM group (n = 22) in a 12-week exercise programme. AT involved 45 min of ergometer training at 70-80% of maximum heart rate, three times a week for both groups. In the AT/IMT group, IMT was performed at 60% of sustained maximal inspiratory pressure (SPImax ) while in the AT/SHAM group it was performed at 10% of SPImax , using a computer biofeedback trainer for 30 min, three times a week. At baseline and at 3 months, patients were evaluated for exercise capacity, lung function, inspiratory muscle strength (PImax ) and work capacity (SPImax ), quality of life (QoL), LVEF and LV diameter, dyspnoea, C-reactive protein (CRP), and NT-proBNP. IMT resulted in a significantly higher benefit in SPImax (P = 0.02), QoL (P = 0.002), dyspnoea (P = 0.004), CRP (P = 0.03), and NT-proBNP (P = 0.004). In both AT/IMT and AT/SHAM groups PImax (P < 0.001, P = 0.02), peak VO2 (P = 0.008, P = 0.04), and LVEF (P = 0.005, P = 0.002) improved significantly; however, without an additional benefit for either of the groups. This randomized multicentre study demonstrates that IMT combined with aerobic training provides additional benefits in functional and serum biomarkers in patients with moderate CHF. These findings advocate for application of IMT in cardiac rehabilitation programmes.

Association between sleep‐disordered breathing, sleep–wake pattern, and cognitive impairment among patients with chronic heart failure

Chronic heart failure (CHF) and sleep-disordered breathing (SDB) are often co-existing problems among the elderly. Apnoeic events may cause cognitive impairment. The aim of the study was to compare sleep and wake patterns, insomnia, daytime sleepiness, and cognitive function in community-dwelling CHF patients, with and without SDB, and to investigate the association between sleep-related factors and cognitive dysfunction. In this cross-sectional observational study, SDB was measured with an ApneaLink device and defined as an apnoea-hypopnoea index (AHI) ≥15/h of sleep. Sleep and wake patterns were measured with actigraphy for 1 week. Insomnia was measured with the Minimal Insomnia Symptom Scale, daytime sleepiness with the Epworth Sleepiness Scale, and cognitive function with a neuropsychological test battery. A total of 137 patients (68% male, median age 72 years, 58% NYHA functional class II) were consecutively included. Forty-four per cent had SDB (AHI ≥15). The SDB group had significantly higher saturation time below 90%, more difficulties maintaining sleep, and lower levels of daytime sleepiness compared with the non-SDB group. Cognitive function and sleep and wake patterns did not differ between the SDB and the non-SDB group. Insomnia was associated with decreased global cognition. The prevalence of cognitive dysfunction was low in this population with predominantly mild to moderate CHF. This might have influenced the lack of associations between cognitive function and SDB. Insomnia was the only sleep-related factor significantly influencing cognition.

Additional use of an aldosterone antagonist in patients with mild to moderate chronic heart failure: a systematic review and meta‐analysis

Aldosterone antagonists (AldoAs) have been used to treat severe chronic heart failure (CHF). There is uncertainty regarding the efficacy of using AldoAs in mild to moderate CHF with New York Heart Association (NYHA) classifications of I to II. This study summarizes the evidence for the efficacy of spironolactone (SP), eplerenone (EP) and canrenone in mild to moderate CHF patients. PubMed, MEDLINE, EMBASE and OVID databases were searched before June 2012 for randomized and quasi-randomized controlled trials assessing AldoA treatment in CHF patients with NYHA classes I to II. Data concerning the study's design, patients' characteristics and outcomes were extracted. Risk ratio (RR) and weighted mean differences (WMD) or standardized mean difference were calculated using either fixed or random effects models. Eight trials involving 3929 CHF patients were included. AldoAs were superior to the control in all cause mortality (RR 0.79, 95% CI 0.66, 0.95) and in re-hospitalization for cardiac causes (RR 0.62, 95% CI 0.52, 0.74), the left ventricular ejection fraction was improved by AldoA treatment (WMD 2.94%, P = 0.52). Moreover, AldoA therapy decreased the left ventricular end-diastolic volume (WMD -14.04 ml, P < 0.00001), the left ventricular end-systolic volume (WMD -14.09 ml, P < 0.00001). A stratified analysis showed a statistical superiority in the benefits of SP over EP in reducing LVEDV and LVESV. AldoAs reduced B-type natriuretic peptide concentrations (WMD -37.76 pg ml(-1), P < 0.00001), increased serum creatinine (WMD 8.69 μmol l(-1), P = 0.0003) and occurrence of hyperkalaemia (RR 1.78, 95% CI 1.43, 2.23). Additional use of AldoAs in CHF patients may decrease mortality and re-hospitalization for cardiac reasons, improve cardiac function and simultaneously ameliorate LV reverse remodelling.

Efficacy and safety of bisoprolol fumarate compared with carvedilol in Japanese patients with chronic heart failure: results of the randomized, controlled, double-blind, Multistep Administration of bisoprolol IN Chronic Heart Failure II (MAIN-CHF II) study

Bisoprolol fumarate (bisoprolol) is a β-blocker widely used to treat chronic heart failure (CHF). However, few studies have compared its efficacy and safety with those of the widely used β-blocker carvedilol in Japanese patients with CHF. We designed a confirmatory trial of bisoprolol using carvedilol as a control drug; however, the trial was discontinued after an off-label use of bisoprolol was approved during the study. Bisoprolol and carvedilol were administered for 32 weeks in 31 and 28 patients, respectively. The mean maintenance doses of bisoprolol and carvedilol were 3.3 and 13.6 mg/day, respectively, and the mean durations of treatment were 188.2 and 172.9 days, respectively. Heart-rate changes were similar in both groups. The mean changes from baseline to Week 32 in left ventricular (LV) ejection fraction (EF) (bisoprolol vs carvedilol groups; 11.7 % ± 8.6 % vs 10.1 % ± 10.5 %), LV end-diastolic volume (-37.5 ± 48.7 vs -24.7 ± 29.4 ml), and LV end-systolic volume (-41.9 ± 43.0 vs -29.3 ± 25.9 ml) revealed a decrease in LV volume and an increase in LVEF in both groups. The cumulative event-free rate for a composite of cardiovascular death or admissions to hospital for worsening of CHF was 92.4 % and 94.7 % in the bisoprolol and carvedilol groups, respectively. Overall, 90.3 % and 85.7 % of patients were titrated up to the maintenance doses of bisoprolol and carvedilol, respectively. Bisoprolol, at half the dose used in other countries, is well tolerated and is as effective as carvedilol for treating Japanese patients with mild to moderate CHF.

Efficacy and safety of a 60-week treatment with candesartan in Japanese patients with mild to moderate chronic heart failure

BackgroundChronic heart failure (CHF) is an increasingly common cardiovascular disease despite recent advances in its diagnosis and management. Methods and resultsA multicenter, open-label study was designed to assess the efficacy and safety of 60-week treatment with candesartan in Japanese patients with mild to moderate CHF. Primary efficacy endpoints were changes from baseline in plasma brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), end-diastolic dimension, and New York Heart Association (NYHA) functional class. Two hundred and eighty-nine eligible patients were divided into 2 groups based on the daily dose at the end of treatment: high-dose (HD, 8mg, N=170) and low-dose (LD, 2 or 4mg, N=119). Neither plasma BNP levels nor LVEF changed from the baseline to the end of treatment in the LD group, whereas BNP significantly improved from 61.6 to 50.1pg/mL (p=0.0005) and LVEF from 57.2 to 60.1% (p=0.0005) in the HD group. The changes in NYHA functional class were comparable between groups: 21.2% improved and 76.3% unchanged in the LD group and 20.6% improved and 79.4% unchanged in the HD group. No safety concerns were observed in either group. ConclusionsHD candesartan was more effective in improving plasma BNP levels and cardiac function than LD in Japanese CHF patients. Both LD and HD candesartan were well tolerated in CHF patients.

Impact of tricuspid regurgitation on survival in patients with chronic heart failure: unexpected findings of a long-term observational study

Tricuspid regurgitation (TR) is common in patients with chronic heart failure (CHF) but its prognostic impact is unclear. A total of 576 consecutive patients with CHF were prospectively included. The impact of moderate and severe (significant) TR on the combined endpoint death/heart transplantation/left ventricular-assist device implantation was assessed. Patients were followed for 5.8 ± 4.2 (maximum 14.4) years. Kaplan-Meier analysis showed a worse outcome of patients with significant TR (P < 0.0001). By multivariable analysis, amino terminal pro B-type natriuretic peptide (NT-proBNP) (P = 0.0028), systolic left ventricular function (LVF) (P = 0.0014), serum sodium, NYHA functional class, systolic blood pressure, right atrial size (all P = 0.0001), but not TR were significantly related with the outcome. However, as soon as the strong interaction between TR and LVF was included in the model, significant TR determined outcome as well (P = 0.0059). Therefore, in a second analysis patients were stratified for LVF. In patients with mildly or moderately impaired LVF, TR was significantly related with the outcome (HR: 1.368, CI: 1.070-1.748, P = 0.0125), whereas in patients with severely depressed LVF it was not (P = 0.1401). As a proof of concept, we additionally stratified patients according to serum NT-proBNP concentrations. In patients with NT-proBNP concentrations below the median (≤ 280 fmol/mL), TR was related with the outcome (HR: 2.512, CI: 1.127-5.597, P = 0.0242) but it was not in patients with NT-proBNP concentrations above the median (P = 0.3935). The prognostic impact of TR depends on the severity of CHF. While TR was significantly related with excess mortality in mild to moderate CHF, it provided no additive value in advanced disease when compared with established risk factors.

Pharmacokinetics of Pentoxifylline and Its Main Metabolites in Patients With Different Degrees of Heart Failure Following a Single Dose of a Modified‐Release Formulation

Pentoxifylline (PTX) is extensively metabolized in the body, and all its 3 plasma metabolites (M1, M4, M5) are pharmacologically active. The authors evaluated the pharmacokinetics of PTX and its metabolites in 20 patients with chronic heart failure (CHF). Eleven had moderate and 9 severe CHF. The time courses of PTX, M1, M4, and M5 plasma levels were determined after oral administration of a sustained-release 600-mg tablet of PTX, and for each compound, AUC, maximal plasma concentration (C(max)), and time to C(max) (T(peak)) were calculated. Compared with patients with moderate CHF, those with severe CHF showed a significant delay in T(peak) of PTX (3.9 vs 1.6 hours) and M5 (5.6 vs 3.6 hours), a 59% significant increase in M5 AUC, and a 56% nonsignificant increase in PTX AUC. In the whole population, the AUCs of PTX, M4, and M5 were inversely correlated with markers of liver function, whereas the AUCs of M4 and M5 were inversely correlated with the creatinine clearance. In view of the kinetic features of slow-release formulations (flip-flop phenomenon), the delay in T(peak) of PTX in patients with severe CHF compared with moderate CHF should be ascribed to a reduced elimination rate.

Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol: Japanese chronic heart failure (J-CHF) study

BackgroundIn chronic heart failure (CHF), it remains unclear whether the minimal dose of beta-blockade is related to survival benefits and which parameter predicts morbidity and mortality. We sought to determine the minimal dose related to survival benefits by comparing the efficacy and safety of three doses of carvedilol and the best predictive parameter for effective outcomes in Japanese patients with CHF. MethodsIn this prospective, randomized, stratified trial, 364 patients with mild to moderate CHF were assigned to a daily carvedilol dose of 2.5, 5, or 20mg, plus optimal standard therapy. FindingsDuring the mean 3-year follow-up, resting heart rate (HR) and BNP were significantly reduced with dose–response relations in the early period but without dose–response relations in the late period. The LVEF and the LVDd were increased and decreased, respectively, without a dose–response relation. No significant difference was seen in the composite primary endpoint of all-cause mortality and hospitalization for cardiovascular diseases and heart failure. Multivariate analysis indicated early decreases in HR and BNP predicted long-term outcomes. However, adverse events increased dose-dependently. Among 237 polymorphisms in 87 heart failure-related genes, the osteopontin G-156 del genotype was associated with an event-free survival rate (Wilcoxon test, P=0.030). ConclusionsA low carvedilol dose is effective if the HR and/or plasma BNP has been reduced. Carvedilol therapy should be guided by reductions in HR and/or BNP, especially by initial HR reduction, but not only by its dose. OPN might be a surrogate genetic marker for long-term event-free survival.

Abstract 19121: Prediction of Sudden Cardiac Death in Patients with Mild to Moderate Chronic Heart Failure: A Comparative Study of Early Repolarization and Fragmented QRS

Background: Identification of patients with chronic heart failure (CHF) at risk for sudden cardiac death (SCD) is an important objective. Early repolarization pattern (ERP) and fragmented QRS (fQRS) on the standard 12-lead ECG have recently been associated with an increased risk of life-threatening ventricular arrhythmias in patients with chronic coronary artery disease. However, there is little information available on the comparison of the prognostic significance for SCD between ERP and fQRS in patients with CHF. Methods: We studied 132 consecutive outpatients (NYHA class: 2.0±0.6), with radionuclide left ventricular ejection fraction less than 40% (30±7%), who were enrolled in our prospective cohort study. All patients underwent the standard 12-lead ECG at enrollment. We assessed the presence of ERP, using the criteria of J-point elevation ≥0.1 mV in at least 2 inferior or lateral leads. fQRS was defined by the presence of &gt;2 notches on the R wave or the S wave and had to be present in &gt;or=2 contiguous inferior (II, III, aVF), lateral (I, aVL, V(6)) or anterior (V(1) to V(5)) leads. The primary endpoint of this study was SCD. Results: At enrollment, 16 and 30 patients had ERP and fQRS, respectively. During the mean follow-up period of 6.7±3.5 yrs, 26 patients had SCD. Kaplan-Meier analysis showed that SCD was observed significantly more frequently in patients with than without ERP (63% vs 14%, p&lt;0.0001), and also in patients with than without fQRS in ≥ 2 territories (anterior and inferior, anterolateral or inferolateral), (45% vs 17%, p=0.044). A multivariate Cox analysis revealed that ERP was significantly and independently associated with SCD (hazard ratio 3.7 (95%CI 1.6-8.6), p=0.002), although fQRS in ≥2 territories showed a significant association with SCD (p=0.034) at univariate analysis . Conclusion: ERP in inferior leads would be more strongly associated with an increased risk of SCD in patients with mild to moderate CHF, in comparison to fragmented QRS.

The Effects of Poloxamer-188 on Left Ventricular Function in Chronic Heart Failure After Myocardial Infarction

Poloxamer-188 (P-188) is a biological membrane sealant that prevents the unregulated entry of Ca into cardiomyocytes and has been shown to have the ability to act as a membrane-repair agent in isolated cardiac myocytes. The purpose of this study was to determine if treatment with P-188 would improve left ventricular (LV) function in a rat chronic heart failure (CHF) model. We ligated the left coronary artery of adult male Sprague-Dawley rats to induce a myocardial infarction (MI). The rats were allowed to recover for 8 weeks until stable CHF was present and treated with a range of P-188 doses [1.5 mg/kg (N = 6), 4.6 mg/kg (N = 11), 15.3 mg/kg (N = 11), and 460 mg/kg (N = 6)] delivered via 30 minutes of intravenous infusion. The rats were randomized to study groups: control, 2 hours, 24 hours, 48 hours, 1 week, and 2 weeks posttreatment (N = 8 in each group). Two weeks after high dose (460 mg/kg) administration, P-188 improved (P < 0.05) left ventricular ejection fraction from 34% to 51%, which persisted over 38 hours and decreased (P < 0.05) LV end systolic diameter from 0.9 ± 0.07 to 0.6 ± 0.08 cm, in the rats with CHF. There was no statistical change in hemodynamics. Additionally, P-188 reduced (P < 0.05) circulating troponin levels 2 weeks after treatment. Treatment with P-188 improves the LV function and partially reverses maladaptive LV remodeling in rats with moderate CHF after MI. These data introduce the idea of using a biological membrane sealant as a new approach to treating CHF after MI.

Long‐Term Prognostic Value of the Right Ventricular Myocardial Performance Index Compared to Other Indexes of Right Ventricular Function in Patients with Moderate Chronic Heart Failure

The ventricular myocardial performance index (MPI) is a feasible echocardiographic parameter for the evaluation of patients with chronic heart failure (CHF). The long-term prognostic role of right ventricular MPI (RV MPI) has been already assessed in patients with more advanced CHF but data are lacking in moderate CHF. The aim of the study is to evaluate the possible prognostic role of RV MPI in moderate CHF patients compared to others traditional RV parameters. From 2003 to 2004 we enrolled 95 consecutive NYHA class II CHF patients (65 males and 30 females), with the mean age of 66 ± 11 years with left ventricular ejection fraction (LVEF) <40%, on optimal medical treatment. All patients were evaluated clinically and by echocardiography with a follow-up of 5 years (combined end point: cardiovascular mortality and hospitalization for HF). RV MPI was 0.45 ± 0.36, tricuspid annular plane systolic excursion was 21 ± 8 mm, RV fractional area change was 42 ± 12%, systolic pulmonary artery pressure was 33 ± 9 mmHg, and acceleration time of pulmonic flow was 115.5 + 22.62 msec. After the 5 year follow-up the total mortality was 24.2% and HF hospitalization rate was 33%. At Cox multivariate analysis only an RV MPI superior to median value (>0.38) and tricuspid annular plane systolic excursion inferior to median value (<18 mm) had shown a significant prognostic role. The RV MPI in a population of moderate CHF showed to have a more long-term powerful prognostic value than other conventional and traditional echocardiographic right ventricular functional parameters.

The Prognostic Value of Estimated Glomerular Filtration Rate, Amino-Terminal Portion of the Pro-Hormone B-Type Natriuretic Peptide and Parameters of Cardiopulmonary Exercise Testing in Patients with Chronic Heart Failure

The aim of this study was to evaluate the prognostic value of renal function in relation to amino-terminal portion of the pro-hormone B-type natriuretic peptide (NT-proBNP) and parameters of cardiopulmonary exercise testing in predicting mortality and morbidity in patients with moderate chronic heart failure (CHF). Sixty-one CHF patients were included in the study. Patients' characteristics were: age 64.3±11.6 years; New York Heart Association class I/II/III: 14/37/10; left ventricular ejection fraction: 0.30±0.13 (%); NT-proBNP: 252.2±348.0 (ng/L); estimated creatinine clearance (e-CC): 73.6±31.4 (mL/min); estimated glomerular filtration rate (e-GFR): 66.1±24.6 (mL/min/1.73 m2); the highest O2 uptake during exercise (VO2-peak): 1.24±0.12 mL/kg/min; VO2/workload: 8.52±1.81 (mL/min/W)]. During follow up (59.5±4.0 months) there were 15 cardiac deaths and 16 patients were hospitalized due to progression of heart failure. NT-proBNP and VO2/workload were independently associated with cardiac death (P=0.007 and P=0.006, respectively). Hospitalization for progressive CHF was only associated with NT-proBNP (P=0.002). The combined cardiac events (cardiac death and hospitalization) were associated with NT-proBNP and VO2/ workload (P=0.007 and P=0.005, respectively). The addition of estimates of renal function (neither serum creatinine nor e-GFR) did not improve the prognostic value for any of the models.In conclusion, in patients with moderate CHF, increased NT-proBNP and reduced VO2/ work-load identify those with increased mortality and morbidity, irrespective of estimates of renal function.

Skeletal muscle microcirculatory abnormalities are associated with exercise intolerance, ventilatory inefficiency, and impaired autonomic control in heart failure

Several skeletal muscle abnormalities have been identified in patients with chronic heart failure (CHF), including endothelial dysfunction. We hypothesized that skeletal muscle microcirculation, assessed by near-infrared spectroscopy (NIRS), is impaired in CHF patients and is associated with disease severity. Eighty-three stable patients with mild-moderate CHF (72 males, mean age 54 ± 14 years, body mass index 26.7 ± 3.4 kg/m(2)) and 8 healthy subjects, matched for age, gender and body mass index, underwent NIRS with the vascular occlusion technique and cardiopulmonary exercise testing (CPET) evaluation on the same day. Tissue oxygen saturation (StO(2), %), defined as the percentage of hemoglobin saturation in the microvasculature compartments, was measured in the thenar muscle by NIRS before, during and after 3-minute occlusion of the brachial artery. Measurements included StO(2), oxygen consumption rate (OCR, %/min) and reperfusion rate (RR, %/min). All subjects underwent a symptom-limited CPET on a cycle ergometer. Measurements included VO(2) at peak exercise (VO(2)peak, ml/kg/min) and anaerobic threshold (VO(2)AT, ml/kg/min), VE/VCO(2) slope, chronotropic reserve (CR, %) and heart rate recovery (HRR(1), bpm). CHF patients had significantly lower StO(2) (75 ± 8.2 vs 80.3 ± 6, p < 0.05), lower OCR (32.3 ± 10.4 vs 37.7 ± 5.5, p < 0.05) and lower RR (10 ± 2.8 vs 15.7 ± 6.3, p < 0.05) compared with healthy controls. CHF patients with RR ≥9.5 had a significantly greater VO(2)peak (p < 0.001), VO(2)AT (p < 0.01), CR (p = 0.01) and HRR(1) (p = 0.01), and lower VE/VCO(2) slope (p = 0.001), compared to those with RR <9.5. In a multivariate analysis, RR was identified as an independent predictor of VO(2)peak, VE/VCO(2) slope and HRR(1). Peripheral muscle microcirculation, as assessed by NIRS, is significantly impaired in CHF patients and is associated with disease severity.

Differences between bisoprolol and carvedilol in patients with chronic heart failure and chronic obstructive pulmonary disease: a randomized trial

Chronic obstructive pulmonary disease (COPD) frequently coexists in patients with chronic heart failure (CHF) and is a key factor for beta blocker underprescription and underdosing. This study compared effects of bisoprolol and carvedilol in patients with both conditions. This was a randomized open-label study, of bisoprolol and carvedilol during initiation and uptitration to target or maximal tolerated dose. Pulmonary function testing, 12-lead electrocardiogram, and N-terminal pro brain natriuretic peptide were measured at baseline and follow-up. We randomized 63 elderly patients (73 ± 9 years, 81% men, left ventricular ejection fraction 33 ± 7%) with mild to moderate CHF (54% New York Heart Assocation class II) and moderate to severe COPD (76% Global initiative for chronic Obstructive Lung Disease stage 2). Target dose was tolerated by 31 (49%) patients and 19 (30%) patients experienced adverse events during follow-up (19% bisoprolol, 42% carvedilol, p = 0.045). Study medication had to be withdrawn in 8 (13%) patients (bisoprolol: 2 due to hypotension, 1 due to bradycardia; carvedilol: 2 due to hypotension and 1 due to wheezing, dyspnoea, and oedema, respectively). Forced expiratory volume in 1(st) second significantly increased in bisoprolol (1561 ± 414 ml to 1698 ± 519 ml, p = 0.046) but not carvedilol (1704 ± 484 to 1734 ± 548, p = 0.44) group. Both agents reduced heart rate (bisoprolol: 75 ± 14 to 68 ± 10, p = 0.007; carvedilol 78 ± 14 to 72 ± 12, p = 0.016) and had no effect on N-terminal pro brain natriuretic peptide. Beta blockers frequently caused adverse events, and thus 49% of patients could tolerate the target dose. Bisoprolol induced demonstrable improvement in pulmonary function and caused less adverse events.

Platelet activation, oxidative stress and overexpression of inducible nitric oxide synthase in moderate heart failure

1. Chronic heart failure (CHF) is a common disabling disorder associated with thromboembolic events, the genesis of which is not yet fully understood. Nitric oxide (NO), derived from the vascular endothelium and platelets, has an important role in the physiological regulation of blood flow. It is generated from the amino acid L-arginine via NO synthase (NOS). 2. The main objective of the present study was to investigate NO production and its relationship with platelet aggregation, oxidative stress, inflammation and related amino acids in patients with moderate CHF. The expression and activity of NOS isoforms were analysed by western blotting and conversion of L-[(3)H]-arginine to L-[(3)H]-citrulline, respectively, in CHF patients (n = 12) and healthy controls (n = 15). Collagen- and ADP-induced platelet aggregation, oxidative stress (thiobarbituric acid-reactive substances (TBARS) formation and superoxide dismutase (SOD) activity) and plasma levels of amino acids and inflammatory markers (fibrinogen and C-reactive protein (CRP)) were also determined. 3. Both collagen- and ADP-induced platelet aggregation were increased in CHF patients compared with controls. Platelets from CHF patients did not show any changes in NOS activity in the presence of overexpression of inducible NOS. Systemic and intraplatelet TBARS production was elevated, whereas SOD activity was decreased in CHF patients. l-arginine plasma concentrations were lower in CHF patients than in controls. Systemic levels of CRP and fibrinogen were increased in CHF patients. 4. The results show that, in patients with moderate CHF, there is platelet activation and reduced intraplatelet NO bioavailability due to oxidative stress, which suggests a role for platelets in the prothrombotic state.

Ischemic stroke history predicts increased cardiovascular mortality in chronic heart failure

To investigate comorbidities that predict cardiac mortality and re-hospitalization in chronic heart failure (CHF) patients. Five hundred eighty patients (mean age 63 ± 13 years, 373 male, 207 female, mean ejection fraction (EF) 26 ± 9%) with mild, moderate or severe CHF [NYHA class II-IV] were included in this prospective observational study. We evaluated all comorbidities such as history of ischemic stroke, coronary artery disease, peripheral arterial disease, chronic obstructive lung disease, hypertension, diabetes mellitus and chronic kidney disease in CHF patients who were hospitalized due to decompensated heart failure in Kocaeli University, Faculty of Medicine's Hospital between January 2003 and July 2009. Cox regression and Kaplan-Meier survival analyses were used to establish predictors of unfavorable outcomes. Of 580 patients 207 (36%) patients died due to cardiovascular reasons. In multivariable Cox regression analysis age (HR-1.06, 95% CI 1.04-1.08, p<0.001), NYHA functional class (HR-3.20 95% CI, 1.90-5.41, p<0.001), history of ischemic stroke (HR-2.48, 95% CI 1.14-5.37, p=0.022), high-sensitive C-reactive protein (HR-1.09, 95% CI, 1.04-1.15, p=0.001), brain natriuretic peptide (HR-1.00, 95% CI 1.00-1.00, p=0.01) and hemoglobin (HR-0.90, 95% CI 0.81-0.99, p=0.038) were independent predictors of cardiac death in the present study. History of ischemic stroke was demonstrated as an important comorbidity that predicts cardiovascular mortality beyond other co-morbidities in CHF patients. NYHA functional class (HR-2.85, 95% CI 1.80-4.65, p<0.001), left ventricular EF [(HR-0.98, 95% CI 0.95-0.99, p=0.039) and ischemic stroke history (HR-2.41, 95% CI 1.15-5.05, p=0.019) were independent predictors for recurrence hospitalization. The stroke history was only predictor showing recurrent hospitalization at least in one year among the other comorbid conditions, which were evaluated during study. History of ischemic stroke may be an important risk factor for increased cardiac mortality and recurrence hospitalization in CHF patients.

Progressive chronic heart failure slows the recovery of microvascular O2pressures after contractions in the rat spinotrapezius muscle

Chronic heart failure (CHF) induces muscle fiber-type specific alterations in skeletal muscle O(2) delivery and utilization during metabolic transitions. As a result, the recovery of microvascular Po(2) (Pmv(O(2))) is prolonged in slow-twitch skeletal muscle but not fast-twitch skeletal muscle in rats with CHF. We tested the hypothesis that CHF slows Pmv(O(2)) recovery in rat skeletal muscle of a mixed fiber-type analogous to human locomotory muscles and that the degree of slowing correlates with central indexes of heart failure. Healthy control [n = 6, left ventricular end-diastolic pressure (LVEDP): 10 ± 1 mmHg], moderate CHF (n = 6, LVEDP: 18 ± 2 mmHg), and severe CHF (n = 4, LVEDP: 34 ± 2 mmHg) female Sprague-Dawley rats had their right spinotrapezius muscles (41% type I, 7% type IIa, and 52% type IIb and d/x) exposed, and Pmv(O(2)) was measured via phosphorescence quenching during 180 s of recovery from 180 s of electrically induced twitch contractions (1 Hz, 4-6 V). CHF progressively slowed the mean response time (MRT; the time to reach 63% of the overall dynamic response) of Pmv(O(2)) recovery (MRT(off); control: 60.2 ± 6.9, moderate CHF: 72.8 ± 6.6, and severe CHF: 109.8 ± 6.6 s, P < 0.05 for all). MRT(off) correlated positively with central hemodynamic (LVEDP: r = 0.76, P < 0.01) and morphological (right ventricle-to-body weight ratio: r = 0.74, P < 0.01; and lung weight-to-body weight ratio: r = 0.79, P < 0.01) indexes of heart failure. The present investigation suggests that slowed Pmv(O(2)) kinetics during recovery in CHF constitutes a mechanistic link between impaired circulatory and metabolic recovery after contractions in CHF.

Functional electrical stimulation of lower limbs in patients with chronic heart failure

Physical training is an important component of therapy for patients with chronic heart failure (CHF) and is considered complementary to their pharmacological treatment. The majority of conventional rehabilitation programs include aerobic training, which has been demonstrated to induce significant beneficial effects on the neurohumoral, immunoreactive and functional status of patients with moderate CHF. Functional electrical stimulation (FES) of skeletal muscles constitutes an alternative training mode with beneficial effects comparable to classical aerobic exercise, suitable for patients with CHF who cannot participate in traditional training programs due to either advanced grades of CHF or the presence of comorbidities. We present a review of the numerous studies evaluating the effects of FES in CHF, focusing on its main effects on skeletal myopathy reversal, exercise tolerance improvement and quality of life modification.