Stable Systolic Chronic Heart Failure Research Articles

Cardiac and Hemodynamic Effects of Acute Phosphodiesterase-1 Inhibition in Human Heart Failure

Introduction Phosphodiesterase-1 (PDE-1) hydrolyzes cyclic adenosine monophosphate and cyclic guanosine monophosphate, key second messenger molecules in cardiac and vascular tissue. Selective PDE-1 inhibition with ITI-214 resulted in systemic vasodilation and positive inotropic effects (inodilator) in a canine heart failure (HF) model with minimal effects on blood pressure. Hypothesis The specific PDE-1 inhibitor, ITI-214, confers inodilator effects in humans with HF with reduced ejection fraction. Methods ITI-214-104 was a Phase Ib/IIa, multi center, double-blind, randomized, placebo-controlled single ascending dose cohort study of ITI-214 in patients with stable chronic systolic HF (NYHA Class II-III, LVEF ≤ 35%) (NCT03387215). Participants were randomized 9:3 to receive either ITI-214 10, 30, or 90 mg or placebo, with transthoracic echocardiography obtained just before and 120 min after dosing. Safety outcomes included supine and orthostatic BP and HR, telemetry events and blood laboratories. Hemodynamic outcomes included mean LV power index (primary outcome), as well as exploratory outcomes: cardiac output, LV volumes, LVEF, effective arterial elastance (Ea), and estimated systemic vascular resistance (SVR). Results Patient mean age was 54 yr, 57% male and 57% Black with mean LVEF 25% (31% had ischemic HF). Cmax occurred at 90 - 120 min, with area under curve increasing with dose escalation. ITI-214 30 mg increased mean LV power index and cardiac output while SVR and MAP decreased at 30 and 90 mg doses at 120 minutes post dose compared to placebo (Figure). Total LV afterload (Ea) followed the same pattern as SVR change. There were 3 orthostatic hypotension and 3 hypotension adverse events, both mild to moderate. There was no change in arrhythmia on continuous telemetry monitoring and no serious adverse events. Conclusion Single-dose ITI-214 confers inodilator effects in humans with systolic HF. These data confirm our previous findings in the canine HF model. Further investigation of acute and chronic PDE-1 inhibition in HF should be considered.

Soluble angiotensin converting enzyme 2 levels in chronic heart failure is associated with decreased exercise capacity and increased oxidative stress-mediated endothelial dysfunction

The aim of this study was to explore the relationship between serum soluble angiotensin converting enzyme 2 (sACE2), parameters of cardiopulmonary exercise testing and plasma asymmetric dimethylarginine (ADMA), a marker of oxidative stress-induced endothelial dysfunction. This has not been previously evaluated. We assessed 50 consecutive ambulatory patients with chronic systolic heart failure and left ventricular ejection fraction (LVEF) ≤45%. Their blood samples were collected for sACE2 and ADMA tests before they underwent symptom-limited cardiopulmonary exercise testing and transthoracic echocardiography. The majority of our study subjects had New York Heart Association functional class II (74%) and III (18%) presentation, and 42% of patients had ischemic etiology. Median sACE2 activity was 10.36 (7.00-14.47) ng/mL and mean ADMA was 0.90 ± 0.22. sACE2 activity was inversely correlated with pVO2 (r = -0.42, P = 0.00283), exercise time (r = -0.35, P = 0.0138) and LVEF (r = -0.548, P < 0.001), and positively correlated with VE/VCO2 slope (r = 0.294, P = 0.0405), ΔDBP (r = 0.315, P = 0.0278), mitral E/Ea ratio (r = 0.442, P = 0.00158) and ADMA levels (r = 0.351, P = 0.0134). Meanwhile, we observed a negative correlation between ADMA and pVO2 (r = -0.424, P = 0.00227) and positive correlations between ADMA and VE/VCO2 slope (r = 0.515, P < 0.001), ΔDBP (r = 0.391, P = 0.00568), mitral E/Ea ratio (r = 0.426, P = 0.00219). In multivariate logistic regression analysis, sACE2 was independently associated with peak oxygen uptake (% predicted) after adjusting for body mass index (BMI) and mitral E/Ea ratio (odds ratio [OR] 0.81 (0.58-0.94), P = 0.041) and associated with oxygen pulse (VO2/HR) (%) after adjusting for age, gender, BMI and mitral E/Ea ratio (OR 0.83 [0.68-0.95], P = 0.025). Therefore in stable chronic systolic heart failure patients, higher sACE2 activity is independently associated with diminished exercise capacity and correlates with elevated systemic oxidative stress-mediated endothelial dysfunction.

Prognostic Impact of Copeptin and Mid-Regional Pro-Adrenomedullin in Chronic Heart Failure with Regard to Comorbidities

The aim of the study is to evaluate the impact of new humoral substances: copeptin and mid- regional proadrenomedullin (MR-proADM) on one-year survival of patients with stable systolic chronic heart failure (CHF) and to compare them with AHEAD score assessing the comorbidities. The FAR NHL (FARmacology and NeuroHumoraL activation) registry is a database of patients with stable CHF (ejection fraction (EF) <50%) treated in specialized HF departments. AHEAD score is a simple bed-side mortality predictive model based on age and comorbidities. Primary endpoint after 1-year follow-up was: death or hospitalization for decompensation of HF or heart transplantation or LVAD implantation. To whole FAR NHL registry, a total amount of 1088 patients were included, in 552 of them the levels of copeptin and MR-proADM were available. Mean age was 65+12 years, mean EF was 31+9%. Patients without primary endpoint were assigned as group A (469 pts), those with the primary endpoint group B (83 pts). There were statistically significant differences between the groups in the levels of copeptin: group A median 15.9 pmol/l (3.4-50.9) vs group B 23.7 pmol/l(5.0-89.44) (p<0.001), MR-proADM: group A median 0.63 nmol/l(0.32-1.34) vs group B 0.74 nmol/l (0.4-1.94) (p<0.001). Relationship of AHEAD score to primary endpoint in the first year of follow-up was not significant, but within 24th month it reached statistical significance: p= 0.017. Patients with higher AHEAD score (more comorbidities) reached more often the primary end-point. The cutt-off value ≥ 23.7 for copeptin had 50.6% sensitivity and 73.3%. The cut –off value for MR-proADM ≥ 0.58 had higher sensitivity 79.5% and lower specificity 42.0%. For both humoral substances there was statistical significant difference for discrimination of patients with primary endpoint in lower AHEAD score groups. However, in the highest AHEAD score the level of these substances lost their predictive value.

Immediate effects of transcutaneous electrical nerve stimulation on six-minute walking test, Borg scale questionnaire and hemodynamic responses in patients with chronic heart failure.

[Purpose] This study examined the immediate effects of transcutaneous electrical nerve stimulation on a six-minute walking test, Borg scale questionnaire and hemodynamic responses in patients with chronic heart failure. [Subjects and Methods] Thirty patients with stable systolic chronic heart failure came to the pathophysiology laboratory three times. The tests were randomly performed in three sessions. In one session, current was applied to the quadriceps muscles of both extremities for 30 minutes and a six-minute walking test was performed immediately afterward. In another session, the same procedure was followed except that the current intensity was set to zero. In the third session, the patients walked for six minutes without application of a current. The distance covered in each session was measured. At the end of each session, the subjects completed a Borg scale questionnaire. [Results] The mean distance traveled in the six-minute walking test and the mean score of the Borg scale questionnaire were significantly different across sessions. The mean systolic and diastolic pressures showed no significant differences across sessions. [Conclusion] The increase in distance traveled during the six-minute walking test and decrease in fatigue after the use of current may be due to a decrease in sympathetic overactivity and an increase in peripheral and muscular microcirculation in these patients.

Immunosenescence in patients with chronic systolic heart failure.

Chronic heart failure (CHF) is characterized by hemodynamic compromise, neurohormonal and immune activation. We sought to examine the presence and severity of immunosenescence and its relation with the stages of CHF. We enrolled 86 consecutive stable systolic CHF patients and examined the relationship of leukocyte and lymphocyte subpopulation counts by flow cytometry with their functional status according to New York Heart Association (NYHA) class. Patients with advanced heart failure were characterized by significantly increased neutrophil and reduced lymphocyte counts. T-helper cells were increased, whereas B-cells and T cytotoxic cells were decreased. T-helper cells exhibited significant differentiation and aging across the NYHA classes; naïve T-cells, CD4 + CD45RA +, were significantly reduced in NYHA Class IV and memory T-cells, CD4 + CD45RO +, were significantly increased. Patients with CHF develop intense T-cell differentiation and aging. The presence of significant immunosenescence in advanced CHF may indicate a population at increased risk for adverse events.

PP-166 The Relationship between Carbohydrate Antigen 125 and Left Ventricular Echocardiographic Parameters in Stable Chronic Systolic Heart Failure Patients: A Comparative Study with NT-pro BNP

PP-166 The Relationship between Carbohydrate Antigen 125 and Left Ventricular Echocardiographic Parameters in Stable Chronic Systolic Heart Failure Patients: A Comparative Study with NT-pro BNP

Nordic Walking May Safely Increase the Intensity of Exercise Training in Healthy Subjects and in Patients with Chronic Heart Failure.

Physical activity in patients with chronic heart failure (HF) improves the exercise capacity and quality of life, and may also reduce mortality and hospitalizations. The greatest benefits are achieved through high-intensity aerobic exercises resulting in a stronger cardiorespiratory response. Nordic walking (NW), a walking technique using two poles and mimicking the movements performed while cross-country skiing, is associated with the involvement of more muscle groups than in the case of classic walking, and should therefore make it possible to increase exercise intensity, resulting in more effective training for patients with HF. The aim of the study was to assess the feasibility and safety of the NW technique, and to compare the effort intensity while walking with and without the NW technique in both healthy subjects and in patients with chronic HF. The study involved 12 healthy individuals (aged 30 ± 10 years, 5 men) and 12 men with stable chronic systolic HF (aged 63 ± 11 years, all categorized in New York Heart Association class II, median LVEF 30%, median peak VO(2) 18.25 mL/kg/min). All the participants completed two randomly assigned submaximal walking tests (one with NW poles and one without) conducted on a level treadmill for 6 min at a constant speed of 5 km/h. Walking with the NW technique was feasible, safe and well tolerated in all subjects. In both the control group and the chronic HF group, walking with the NW technique increased peak VO(2), RER, VE, PET CO(2), HR and SBP over walking without the poles; and the fatigue grade according to the abridged Borg scale was higher. Dyspnea did not increase significantly with the NW technique. The NW technique can increase the intensity of aerobic training in a safe and well-tolerated way in both healthy individuals and in patients with chronic HF.

Carvedilol Compared With Metoprolol Succinate in the Treatment and Prognosis of Patients With Stable Chronic Heart Failure: Carvedilol or Metoprolol Evaluation Study.

β-Blockers exert a prognostic benefit in the treatment of chronic heart failure. Their pharmacological properties vary. The only substantial comparative trial to date-the Carvedilol or Metoprolol European Trial-has compared carvedilol with short-acting metoprolol tartrate at different dose equivalents. We therefore addressed the relative efficacy of equal doses of carvedilol and metoprolol succinate on survival in multicenter hospital outpatients with chronic heart failure. Four thousand sixteen patients with stable systolic chronic heart failure who were using either carvedilol or metoprolol succinate were identified in the Norwegian Heart Failure Registry and The Heart Failure Registry of the University of Heidelberg, Germany. Patients were individually matched on both the dose equivalents and the respective propensity scores for β-blocker treatment. During a follow-up for 17 672 patient-years, it was found that 304 (27.2%) patients died in the carvedilol group and 1066 (36.8%) in the metoprolol group. In a univariable analysis of the general sample, metoprolol therapy was associated with higher mortality compared with carvedilol therapy (hazard ratio, 1.49; 95% confidence interval, 1.31-1.69; P<0.001). This difference was not seen after multivariable adjustment (hazard ratio, 0.93; 95% confidence interval, 0.57-1.50; P=0.75) and adjustment for propensity score and dose equivalents (hazard ratio, 1.06; 95% confidence interval, 0.94-1.20; P=0.36) or in the propensity and dose equivalent-matched sample (hazard ratio, 1.00; 95% confidence interval, 0.82-1.23; P=0.99). These results were essentially unchanged for all prespecified subgroups. In outpatients with chronic heart failure, no conclusive association between all-cause mortality and treatment with carvedilol or metoprolol succinate was observed after either multivariable adjustment or multilevel propensity score matching.

Biological variation, reference change value (RCV) and minimal important difference (MID) of inspiratory muscle strength (PImax) in patients with stable chronic heart failure.

Despite the widespread application of measurements of respiratory muscle force (PImax) in clinical trials there is no data on biological variation, reference change value (RCV), or the minimal important difference (MID) for PImax irrespective of the target cohort. We addressed this issue for patients with chronic stable heart failure. From the outpatients' clinic of the University of Heidelberg we retrospectively selected three groups of patients with stable systolic chronic heart failure (CHF). Each group had two measurements of PImax: 90 days apart in Group A (n=25), 180days apart in Group B (n=93), and 365days apart in Group C (n=184). Stability was defined as (a) no change in NYHA class between visits and (b) absence of cardiac decompensation 3months prior, during, and 3months after measurements. For each group, we determined within-subject (CVI), between-subject (CVG), and total (CVT) coefficient of variation (CV), the index of individuality (II), RCV, reliability coefficient, and MID of PImax. CVT was 8.7, 7.5, and 6.9% for groups A, B, and C, respectively. The II and RCV were 0.21, 0.20, 0.16 and 13.6, 11.6, 10.8%, respectively. The reliability coefficient and MID were 0.83, 0.87, 0.88 and 1.44, 1.06, 1.12kPa, respectively. Results were similar between age, gender, and aetiology subgroups. In patients with stable CHF, measurements of PImax are highly stable for intervals up to 1year. The low values for II suggest that evaluation of change in PImax should be performed on an individual (per patient) basis. Individually significant change can be assumed beyond 14% (RCV) or 1.12kPa (MID).

Minimal important difference for 6-minute walk test distances among patients with chronic heart failure

BackgroundThe 6-minute walk test (6WT) is an established tool in the assessment of endurance and prognosis in patients with chronic heart failure (CHF). For these patients there is very limited data on biological variation of 6WT distances. We determined the minimal important difference (MID) for the 6WT in patients with stable systolic CHF. MethodsTwo cohorts of patients with stable systolic CHF were included from the outpatients' clinic of the University of Heidelberg. In these cohorts, two 6WT measurements were performed – in cohort 1 (n=461) 180days and in cohort 2 (n=512) 365days apart. Stability was defined as the absence of clinical events (3months before the first test, between both tests, and 6months after the second test) and stability of symptoms (NYHA) between tests. Using a standard error of measurement (SEM)-based approach, we determined the MID for both cohorts. ResultsThe intraclass correlation coefficient was 0.89 at 180days and 0.88 at 365days. The results were consistent for groups stratified for age, gender, etiology of CHF, and individual NYHA class. The MID for the 6WT in stable CHF patients was 35m and 37m between presentation and 180 and 365days, respectively. ConclusionSubmaximal exercise capacity as represented by the 6WT varies little in stable CHF patients for up to 1-year intervals. The MID for changes in 6WT values in patients with stable CHF over a period of 6 to 12months is ~36m.

Efficacy and safety of functional electrical stimulation of lower limb muscles in elderly patients with chronic heart failure: A pilot study

Exercise training is an established modality in chronic heart failure. Functional electrical stimulation (FES) is an effective alternative mode of training in patients unwilling or unable to exercise; however, it has not been investigated in elderly patients. We sought to investigate the effects of FES on functional status, quality of life, emotional status and endothelial function in chronic heart failure patients aged 70 years or higher. Thirty patients with stable systolic chronic heart failure (mean age 75 ± 3 years, New York Heart Association (NYHA) class II/III, 37%/63%) randomly underwent a six-week FES training programme or placebo. Questionnaires addressing quality of life (Kansas City Cardiomyopathy Questionnaire (KCCQ), functional and overall) and emotional stress (Zung self-rating depression scale (SDS), Beck Depression Inventory (BDI)), as well as endothelial function (flow-mediated dilatation) were assessed at baseline and upon protocol completion. A significant improvement in NYHA class (p=0.005), KCCQ-functional (F=68.6, p for interaction<0.001), KCCQ-overall (F=66.9, p<0.001), BDI (F=66.3, p<0.001) and Zung SDS (F=95.1, p<0.001) was observed in the FES group compared to placebo. Patients in the FES group also had a significant increase in flow-mediated dilatation compared with placebo (F=59.1, p<0.01). FES-induced per cent change in flow-mediated dilatation was significantly correlated with respective per cent change in KCCQ functional (r=0.386, p=0.039). In this pilot study, FES effectively improved functional status, quality of life, motional stress and endothelial function in elderly chronic heart failure patients and warrants further investigation in this particular group of patients.

Risk following hospitalization in stable chronic systolic heart failure

We explored the impact of being hospitalized due to worsening heart failure (WHF) or a myocardial infarction (MI) on subsequent mortality in a large contemporary data set of patients with stable chronic systolic heart failure (HF). A total of 6558 patients with stable systolic HF, 6505 with analysable data, with an EF of ≤35%, who were included in the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), were followed for a median of 22.9 months with respect to hospitalizations and vital status. Among the 1288 patients who had at least one hospitalization due to WHF or MI, 455 (35.3%) died during follow-up compared with 600 (11.5%) among patients not hospitalized for these reasons. The risk for death was highest in the early phase after hospitalization. The risk declined rapidly during the first month but remained 3.5-fold (95% confidence interval 2.3-5.1) increased at 18 months after a first WHF hospitalization and 8.8-fold (95% confidence interval 3.6-21.6) increased at 18 months after a first MI hospitalization. The present study confirms previous findings that in patients with stable chronic systolic HF, a hospitalization for WHF or MI is associated with substantially increased risk for subsequent death even with contemporary extensive background pharmacological therapy. The risk is most pronounced in the early phase of hospitalization but remains elevated even after 18 months. Preventing HF hospitalization appears as an important therapeutic objective in such patients, and a hospitalization for WHF or MI should lead to a careful therapeutic reassessment.

Dynamic pulmonary hyperinflation occurs without expiratory flow limitation in chronic heart failure during exercise

To assess the occurrence of tidal expiratory flow limitation (EFL) and/or dynamic pulmonary hyperinflation (DH) in chronic heart failure (CHF) during exercise 15 patients with stable systolic CHF, aged 69±6yr, underwent pulmonary function testing and incremental cardio-pulmonary exercise testing. They subsequently performed constant load exercise testing at 30, 60 and 90% of respective maximum workload. At each step the presence of EFL, by negative expiratory pressure technique, and changes in inspiratory capacity (IC) were assessed. Ejection fraction amounted to 36±6% and V˙O2, peak (77±19% pred.) was reduced. EFL was absent at any step during constant load exercise. In 6 patients IC decreased more than 10% pred. at highest step. Only in these patients TLC, FRC, RV FEF25–75% and DLCO were decreased at rest. V˙O2, peak correlated with DLCO, TLC and IC at rest and with IC (r2=0.59; p<0.001) and decrease in IC (r2=0.44; p<0.001) at 90% of maximum workload. During exercise CHF patients do not exhibit EFL, but some of them develop DH that is associated with lower V˙O2, peak.

Serum levels of microRNAs in patients with heart failure

Diagnosis and risk stratification of patients with heart failure remain a challenge. The small non-coding RNAs known as microRNAs regulate gene expression and seem to play an important role in the pathogenesis of heart failure. In the current study, we aim to characterize the levels of microRNAs in the sera of chronic systolic heart failure patients vs. controls and assess the possible correlation between elevation in the levels of specific microRNAs and clinical prognostic parameters in heart failure patients. The levels of 186 microRNAs were measured in the sera of 30 stable chronic systolic heart failure patients and 30 controls using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The differences in microRNA levels between the two groups were characterized, and a score, based on the levels of four specific microRNAs with the most significant increase in the heart failure group (miR-423-5p, miR-320a, miR-22, and miR-92b), was defined. The score was used to discriminate heart failure patients from controls with a sensitivity and specificity of 90%. Moreover, in the heart failure group, there was a significant association between the score and important clinical prognostic parameters such as elevated serum natriuretic peptide levels, a wide QRS, and dilatation of the left ventricle and left atrium (r = 0.63, P = 3e-4; P = 0.009; P = 0.03; and P = 0.01, respectively). Elevated serum levels of specific microRNAs: miR-423-5p, miR-320a, miR-22, and miR-92b, identify systolic heart failure patients and correlate with important clinical prognostic parameters.

High-Intensity Interval Exercise in Chronic Heart Failure: Protocol Optimization

BackgroundThere are little data on the optimization of high-intensity aerobic interval exercise (HIIE) protocols in patients with chronic heart failure (CHF). Therefore, we compared acute cardiopulmonary responses to 4 different HIIE protocols to identify the optimal one. Methods and ResultsTwenty men with stable systolic CHF performed 4 different randomly ordered single HIIE sessions with measurement of gas exchange. For all protocols (A, B, C, and D) exercise intensity was set at 100% of peak power output (PPO). Interval duration was 30 seconds (A and B) or 90 seconds (C and D), and recovery was passive (A and C) or active (50% of PPO in B and D). Time spent above 85% of VO2peak and time above the ventilatory threshold were similar across all 4 HIIE protocols. Total exercise time was significantly longer in protocols with passive recovery intervals (A: 1,651 ± 347 s; C: 1,574 ± 382 s) compared with protocols with active recovery intervals (B: 986 ± 542 s; D: 961 ± 556 s). All protocols appeared to be safe, with exercise tolerance being superior during protocol A. ConclusionAmong the 4 HIIE protocols tested, protocol A with short intervals and passive recovery appeared to be superior.

Iron Deficiency Predicts Impaired Exercise Capacity in Patients With Systolic Chronic Heart Failure

Background Iron is an indispensable element of hemoglobin, myoglobin, and cytochromes, and, beyond erythropoiesis, is involved in oxidative metabolism and cellular energetics. Hence, iron deficiency (ID) is anticipated to limit exercise capacity. We investigated whether ID predicted exercise intolerance in patients with systolic chronic heart failure (CHF). Methods and Results We prospectively studied 443 patients with stable systolic CHF (age 54 ± 10 years, males 90%, ejection fraction 26 ± 7%, New York Heart Association Class I/II/III/IV 49/188/180/26). ID was defined as: serum ferritin <100 μg/L or serum ferritin 100–300 μg/L with serum transferrin saturation <20%. Exercise capacity was expressed as peak oxygen consumption (VO 2) and ventilatory response to exercise (VE-VCO 2 slope). ID was present in 35 ± 4% (±95% confidence interval) of patients with systolic CHF. Those with ID had reduced peak VO 2 and increased VE-VCO 2 slope as compared to subjects without ID (peak VO 2: 13.3 ± 4.0 versus 15.3 ± 4.5 mL•min•kg, VE-VCO 2 slope: 50.9 ± 15.8 versus 43.1 ± 11.1, respectively, both P < .001, P < .05). In multivariable models, the presence of ID was associated with reduced peak VO 2 (β = −0.14, P < .01 P < .05) and higher VE-VCO 2 slope (β = 0.14, P < .01 P < .05), adjusted for demographics and clinical variables. Analogous associations were found between serum ferritin, and both peak VO 2 and VE-VCO 2 slope ( P < .05). Conclusions ID independently predicts exercise intolerance in patients with systolic CHF, but the strength of these associations is relatively weak. Whether iron supplementation would improve exercise capacity in iron-deficient subjects requires further studies.

Improved insulin sensitivity by the angiotensin receptor antagonist irbesartan in patients with systolic heart failure: A randomized double-blinded placebo-controlled study

BackgroundImpaired insulin sensitivity is common in patients with chronic systolic heart failure (CHF) and contributes to symptomatic status and impaired prognosis. A specific metabolic effect to improve insulin sensitivity in diabetic patients has been reported for some but not all angiotensin II-receptor antagonists. We aimed to test the ancillary metabolic effect of irbesartan on insulin sensitivity in patients with CHF. Methods and participantsIn this placebo-controlled double-blinded study 36 non-diabetic patients with stable ischemic CHF (age 63±9years, peak VO2 16.6±4.8ml/kg/min, LVEF 32±9%) were randomized to irbesartan 300mg/d vs placebo on top of standard CHF therapy. Body composition (dual energy X-ray absorptiometry), clinical status, peripheral vasodilator capacity (plethysmography) and neuroendocrine and metabolic profiles were assessed. Primary endpoint was the change of whole body insulin sensitivity after 4months of treatment assessed by intravenous glucose tolerance testing and minimal modeling. ResultsInsulin sensitivity improved by 26% (p<0.001) in the irbesartan group, but not in the placebo group (treatment effect: 1.044min−1·μU·ml−1·104; 95%CI 0.45 to 1.64, p=0.0026). Treatment effects on systolic and diastolic blood pressure were −11 (95%CI −21 to −1)mmHg and −8 (95%CI −15 to −3)mmHg, respectively. Peripheral vasodilator capacity improved by 14% (p=0.016). Change in insulin sensitivity correlated with increased vasodilator capacity (R=0.47, p=0.021). Body composition and clinical status were not different after 4months of therapy. Also adiponectin, resistin, cytokine profile, and asymmetric dimethylarginine (ADMA) were not changed after this short-term intervention. ConclusionTherapy with irbesartan improved insulin sensitivity in patients with chronic heart failure. Improved peripheral vasodilator capacity may contribute to the metabolic effect. (Clinical trials identifier: NCT00347087).

Is there an additional benefit of serial NT-proBNP measurements in patients with stable chronic heart failure receiving individually optimized therapy?

The role of serial NT-proBNP measurements in patients suffering from chronic systolic heart failure (CHF) who already receive individually optimized pharmacotherapy is still unresolved. NT-proBNP was assessed at baseline and at 6months follow-up in 504 stable CHF patients treated with individually optimized pharmacotherapy. After assessment of clinical stability at 6months, patients were followed up for at least 1year. The combined primary endpoint was defined as death, hospitalization due to cardiac reasons or heart transplantation in 1-year follow-up. We stratified our patients according to two principles: first, a percent change of value (CV) between the first and second measurement of NT-proBNP and secondly, the transformed logarithm of NT-proBNP measured at 6months. During the follow-up period of 1year, 50 patients (9.9%) reached the combined primary endpoint. Stratification according to percentage CV was less accurate in predicting endpoint-free survival compared to a classification in categories of lnNT-proBNP measured at 6months (ROC AUC=0.615; 95% CI 0.525-0.70 vs. ROC AUC=0.790; 95% CI 0.721-0.856, respectively). When entered into proportional hazard regression analysis, lnNT-proBNP measured at 6months remained an independent predictor of the combined primary endpoint with an associated HR of 2.53 (95% CI 1.385-4.280). To date, this is the largest analysis of serial NT-proBNP measurements in patients with CHF receiving individually optimized medical therapy. These data suggest that a single NT-proBNP measurement after 6months in stable clinical conditions may have higher predictive value than stratification of change in serial measurements.

Coenzyme Q10 Terclatrate and Creatine in Chronic Heart Failure: A Randomized, Placebo‐Controlled, Double‐Blind Study

Studies have suggested that micronutrient deficiency has some role in the progression of chronic heart failure (CHF). Oral supplementation with coenzyme Q(10) (CoQ(10)) and creatine may reduce mitochondrial dysfunction that contributes to impaired physical performance in CHF. We conducted a randomized, double-blind, placebo-controlled trial to determine the effect of a mixture of water-soluble CoQ(10) (CoQ(10) terclatrate; Q-ter) and creatine on exercise tolerance and health-related quality of life. Exercise tolerance was measured as total work capacity (kg·m) and peak oxygen consumption (VO(2), mL/min/kg), both from a cardiopulmonary exercise test. Health-related quality of life was measured by the Sickness Impact Profile (SIP) in CHF secondary to left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 35%). After baseline assessment, 67 patients with stable CHF were randomized to receive Q-ter 320 mg + creatine 340 mg (n = 35) or placebo (n = 32) once daily for 8 weeks. At multivariate analysis, 8-week peak VO(2) was significantly higher in the active treatment group than in the placebo group (+1.8 ± 0.9 mL/min/kg, 95% CI: 0.1-3.6, P < 0.05). No untoward effects occurred in either group. This study suggests that oral Q-ter and creatine, added to conventional drug therapy, exert some beneficial effect on physical performance in stable systolic CHF. Results may support the design of larger studies aimed at assessing the long-term effects of this treatment on functional status and harder outcomes.

Deficiencies in circulating testosterone and dehydroepiandrosterone sulphate, and depression in men with systolic chronic heart failure

Elderly men with androgen deficiencies are prone to develop late-onset depression. We investigated links between circulating androgens and depression, and their combined impact on outcome in men with chronic heart failure (CHF). Serum total testosterone (TT) and dehydroepiandrosterone sulphate (DHEAS) were measured using immunoassays in 163 men with stable systolic CHF [age: 60 +/- 10 years, NYHA class (I/II/III/IV): 27/84/46/6] and 316 healthy men. Depression was assessed using Beck Depression Inventory (BDI) and defined as BDI > or =16 points. In men with CHF, reduced TT and DHEAS, advanced NYHA class, elevated N-terminal pro-B type natriuretic peptide (NT-proBNP), reduced glomerular filtration rate, and reduced haemoglobin independently predicted severity of depressive symptoms (all P < 0.05). Depression was present in 20, 37 and 77% of men with no androgen deficiency, either TT or DHEAS deficiency, and both androgen deficiencies, respectively (P < 0.0001). During follow-up (median: 28 months), there were 87 (53%) cardiovascular deaths or unplanned hospitalizations. TT and DHEAS deficiencies (defined as < or = the 10th percentile of serum androgen levels in healthy controls) and BDI > or =16 points independently predicted unfavourable outcome (all P < 0.05). TT and DHEAS deficiencies predict severity of depression in men with CHF. Depression and combined androgen deficiencies are independently related to poor outcome in these patients.