Cardiothoracic ratio from postero-anterior chest radiographs: a simple, reproducible and independent marker of disease severity and outcome in adults with congenital heart disease.

OBJECTIVE: The wide spectrum of intracardiac anatomy and reparative surgery available for adults with congenital heart disease (ACHD) makes uniform measurement of cardiac size and disease severity challenging. The aim of this study was to assess the prognostic potential of cardiothoracic ratio, a simple marker of cardiomegaly, in a large cohort of ACHD. PATIENTS AND SETTING: Chest radiographs from 3033 ACHD patients attending our institution between 1998 and 2007 and 113 normal controls of similar age were analyzed blindly. DESIGN: Cardiothoracic ratio derived from plain postero-anterior chest radiographs, was compared between ACHD patients and controls, different diagnostic subgroups and different functional classes. Relationship between cardiothoracic ratio and survival was assessed using Cox regression. RESULTS: Average cardiothoracic ratio in ACHD was 52.0±7.6% (over 50% in 56.4%), significantly higher in all ACHD diagnostic subgroups compared to controls (42.3±4.0%, p<0.0001) and highest in the "complex" cardiac anatomy, Ebstein's anomaly and Eisenmenger subgroups. Cardiothoracic ratio related to functional class, but was high even in asymptomatic patients. During a median follow-up of 4.2years, 164 patients died. Patients with a cardiothoracic ratio >55% had an 8-fold increased risk of death compared to those in the lowest tertile (<48%). Even patients with mildly increased cardiothoracic ratio (48-55%) had an adjusted 3.6-fold increased mortality compared to the lowest tertile. CONCLUSIONS: Cardiothoracic ratio derived from postero-anterior chest radiographs is a simple, and reproducible marker, which relates to functional class and predicts independently mortality risk in ACHD patients.

Suppression of erythropoiesis in patients with chronic heart failure and anaemia of unknown origin: evidence of an immune basis.

AIMS: Anaemia is a prevalent and adverse comorbidity in chronic heart failure (CHF) but its origins are frequently elusive. Diffuse inflammation is also prominent in CHF and a potent inhibitor of erythrocyte production. We tested the hypothesis that unexplained anaemia in CHF might be subsequent to diminished erythropoiesis as a result of an immune-mediated suppression of erythroid colony formation. METHODS: We studied 61 CHF patients and 20 healthy control subjects. Circulating primitive haematopoietic (CD34(+)) and erythroid precursor cells were quantified by flow cytometry. Circulating erythroid progenitors (BFU-E) were cultured in methylcellulose in the presence and absence of monocytes and sera, and with anti-TNFα neutralising antibodies. RESULTS: Despite higher erythropoietin levels, anaemic patients exhibited lower absolute reticulocyte counts and reticulocyte production indices (P<0.001) than non-anaemic patients and healthy controls. Diminished erythropoiesis was paralleled by attenuated circulating CD34(+), erythroid progenitor and precursor cells in anaemic patients (all P<0.01). Depletion of monocytes from cultures derived only from anaemic patients enhanced BFU-E growth (P=0.03). Only the addition of monocytes and sera from anaemic patients suppressed autologous or allogeneic BFU-E colony formation (P=0.02). Serum TNFα levels were highest in anaemic patients and anti-TNFα neutralising antibodies partly abrogated the inhibitory effects of anaemic sera on erythroid colony growth (P=0.03). CONCLUSION: Unexplained anaemia in patients with CHF results partly from suppressed erythropoiesis and monocytes, via a direct effect of TNFα on erythroid cells, orchestrate a degree of this suppression.

Erythropoietin resistance contributes to anaemia in chronic heart failure and relates to aberrant JAK-STAT signal transduction.

BACKGROUND: Chronic heart failure (CHF) patients are frequently anaemic despite elevated endogenous erythropoietin (Epo) levels. We tested the hypothesis that this might be due to Epo resistance and investigated whether any defects apparent were due to Epo receptor (EpoR) downregulation and/or impaired Epo-induced signal transduction. METHODS: We studied 28 CHF patients (age 64 ± 10 yrs, LVEF 29 ± 9%, 89% male) and 12 healthy controls (65 ± 11 yrs, 75% male). Circulating erythroid progenitors (BFU-E) were cultured with 0, 1, 3 and 9 U/mL Epo. Circulating erythroblast surface EpoR and intracellular phosphorylated Signal Transducer and Activator of Transcription (phosphoSTAT)-5 expression were determined by flow cytometry. RESULTS: Whilst BFU-E from control and non-anaemic subjects required only 3 U/mL Epo to significantly increase their numbers from baseline (1 U/mL), those from anaemic patients required 9 U/mL Epo. Lower Epo sensitivities related to higher interleukin-6 (r=-0.41, P=0.01) and soluble tumour necrosis factor receptor 2 (r=-0.38, P=0.02) levels. EpoR-positive cells were more abundant in anaemic patients (P<0.001). Although erythroblasts from anaemic patients exhibited higher baseline EpoR and phosphoSTAT5 expression (all P<0.05), Epo stimulation triggered significant increases in phosphoSTAT5 levels only in erythroblasts from control subjects and not in those from anaemic patients. CONCLUSION: The responsiveness of erythroid cells to Epo is diminished in anaemic CHF patients. This is not due to EpoR downregulation but relates to a profound blunting of Epo-induced JAK-STAT signalling. Whilst residual Epo sensitivity can be exploited clinically with erythropoietic agents, targeting the mechanisms underlying Epo resistance in CHF may provide greater efficacy.

Diuretics for heart failure.

BACKGROUND: Chronic heart failure is a major cause of morbidity and mortality worldwide. Diuretics are regarded as the first-line treatment for patients with congestive heart failure since they provide symptomatic relief. The effects of diuretics on disease progression and survival remain unclear. OBJECTIVES: To assess the harms and benefits of diuretics for chronic heart failure SEARCH METHODS: Updated searches were run in the Cochrane Central Register of Controlled Trials in The Cochrane Library (CENTRAL Issue 1 of 4, 2011), MEDLINE (1966 to 22 February 2011), EMBASE (1980 to 2011 Week 07) and HERDIN database (1990 to February 2011). We hand searched pertinent journals and reference lists of papers were inspected. We also contacted manufacturers and researchers in the field. No language restrictions were applied. SELECTION CRITERIA: Double-blinded randomised controlled trials of diuretic therapy comparing one diuretic with placebo, or one diuretic with another active agent (e.g. ACE inhibitors, digoxin) in patients with chronic heart failure. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted the data and assessed the eligibility and methodological quality of each trial. Extracted data were analysed by determining the odds ratio for dichotomous data, and difference in means for continuous data, of the treated group compared with controls. The likelihood of heterogeneity of the study population was assessed by the Chi-square test. If there was no evidence of statistical heterogeneity and pooling of results was clinically appropriate, a combined estimate was obtained using the fixed-effects model. MAIN RESULTS: This update has not identified any new studies for inclusion. The review includes 14 trials (525 participants), 7 were placebo-controlled, and 7 compared diuretics against other agents such as ACE inhibitors or digoxin. We analysed the data for mortality and for worsening heart failure. Mortality data were available in 3 of the placebo-controlled trials (202 participants). Mortality was lower for participants treated with diuretics than for placebo, odds ratio (OR) for death 0.24, 95% confidence interval (CI) 0.07 to 0.83; P = 0.02. Admission for worsening heart failure was reduced in those taking diuretics in two trials (169 participants), OR 0.07 (95% CI 0.01 to 0.52; P = 0.01). In four trials comparing diuretics to active control (91 participants), diuretics improved exercise capacity in participants with CHF, difference in means WMD 0.72 , 95% CI 0.40 to 1.04; P < 0.0001. AUTHORS' CONCLUSIONS: The available data from several small trials show that in patients with chronic heart failure, conventional diuretics appear to reduce the risk of death and worsening heart failure compared to placebo. Compared to active control, diuretics appear to improve exercise capacity.

Ursodeoxycholic acid in patients with chronic heart failure: a double-blind, randomized, placebo-controlled, crossover trial.

OBJECTIVES: This study sought to assess the effects of ursodeoxycholic acid (UDCA) on endothelial function and inflammatory markers in patients with chronic heart failure (CHF). BACKGROUND: Endothelial dysfunction is commonly observed in patients with CHF, and it contributes to the limitation in exercise capacity that accompanies this condition. Bacterial lipopolysaccharide may trigger proinflammatory cytokine release and promote further endothelial dysfunction. UDCA, a bile acid used in the treatment of cholestatic liver disease, has anti-inflammatory and cytoprotective properties and may contribute to the formation of mixed micelles around lipopolysaccharide. These properties may help to improve peripheral blood flow in patients with CHF. METHODS: We performed a prospective, single-center, double-blind, randomized, placebo-controlled crossover study of UDCA in 17 clinically stable male patients with CHF (New York Heart Association functional class II/III, left ventricular ejection fraction <45%). Patients received in random order 500 mg UDCA twice daily for 4 weeks and placebo for another 4 weeks. The primary endpoint was post-ischemic peak peripheral arm blood flow as assessed by strain-gauge plethysmography. RESULTS: Sixteen patients completed the study. UDCA was well tolerated in all patients. Compared with placebo, UDCA improved peak post-ischemic blood flow in the arm (+18%, p = 0.038), and a trend for improved peak post-ischemic blood flow in the leg was found (+17%, p = 0.079). Liver function improved: compared with placebo, levels of γ-glutamyl transferase, aspartate transaminase, and soluble tumor necrosis factor α receptor 1 were lower after treatment with UDCA than after placebo (all p < 0.05). There was no change in 6-min walk test or New York Heart Association functional class, and levels of tumor necrosis factor α and interleukin-6 were unchanged or increased compared with placebo. CONCLUSIONS: UDCA is well tolerated in patients with CHF. UDCA improves peripheral blood flow and is associated with improved markers of liver function.

Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival.

OBJECTIVES: The aim of this study was to comprehensively delineate iron metabolism and its implications in patients with chronic heart failure (CHF). BACKGROUND: Iron deficiency is an emerging therapeutic target in CHF. METHODS: Iron and clinical indexes were quantified in 157 patients with CHF. RESULTS: Several observations were made. First, iron homeostasis was deranged in anemic and nonanemic subjects and characterized by diminished circulating (transferrin saturation) and functional (mean cell hemoglobin concentration) iron status in the face of seemingly adequate stores (ferritin). Second, while iron overload and elevated iron stores were rare (1%), iron deficiency (transferrin saturation <20%) was evident in 43% of patients. Third, disordered iron homeostasis related closely to worsening inflammation and disease severity and strongly predicted lower hemoglobin levels independently of age, sex, erythrocyte sedimentation rate, New York Heart Association (NYHA) functional class, and creatinine. Fourth, the etiologies of anemia varied with disease severity, with an iron-deficient substrate (anemia of chronic disease and/or iron-deficiency anemia) evident in 16%, 72%, and 100% of anemic NYHA functional class I or II, III, and IV patients, respectively. Although anemia of chronic disease was more prevalent than iron-deficiency anemia, both conditions coexisted in 17% of subjects. Fifth, iron deficiency was associated with lower peak oxygen consumption and higher ratios of ventilation to carbon dioxide production and identified those at enhanced risk for death (hazard ratio: 3.38; 95% confidence interval: 1.48 to 7.72; p = 0.004) independently of hemoglobin. Nonanemic iron-deficient patients had a 2-fold greater risk for death than anemic iron-replete subjects. CONCLUSIONS: Disordered iron homeostasis in patients with CHF relates to impaired exercise capacity and survival and appears prognostically more ominous than anemia.

SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure.

BACKGROUND: Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca(2+)) leak, cellular triggered activity, and ventricular arrhythmias in the failing heart. METHODS AND RESULTS: We studied the influence of SERCA2a gene therapy on ventricular arrhythmogenesis in a rat chronic heart failure model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and catecholamine-induced arrhythmias in vivo. SERCA2a gene therapy also reduced susceptibility to reentry arrhythmias in ex vivo programmed electrical stimulation studies. Subcellular Ca(2+) homeostasis and spontaneous SR Ca(2+) leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR Ca(2+) leak was reduced after SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalization of SR Ca(2+) load. SERCA2a reduced ryanodine receptor phosphorylation, thereby resetting SR Ca(2+) leak threshold, leading to reduced triggered activity in vitro. Both indirect effects of reverse remodeling and direct SERCA2a effects appear to underlie the antiarrhythmic action. CONCLUSIONS: SERCA2a gene therapy stabilizes SR Ca(2+) load, reduces ryanodine receptor phosphorylation and decreases SR Ca(2+) leak, and reduces cellular triggered activity in vitro and spontaneous and catecholamine-induced ventricular arrhythmias in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to arrhythmias and may represent a novel antiarrhythmic strategy in heart failure.

Impairment of autonomic reactivity is a feature of heart failure whether or not the left ventricular ejection fraction is normal.

BACKGROUND: Autonomic dysfunction (AD) is associated with morbidity and mortality in patients with systolic heart failure (SHF). The extent of AD when LV ejection fraction is preserved (HF-NEF), is unclear. Our objectives were: 1) quantitative assessment of autonomic function in SHF and HF-NEF; and 2) exploration of relationships among AD, symptoms and cardiac function. METHODS: This was an observational study of patients newly referred from primary care with a heart failure diagnosis; 21 SHF, 20 HF-NEF patients and 21 normal subjects were recruited. All subjects underwent clinical evaluation, 6-minute walk test (6 MWT), Minnesota Questionnaire (MLWHFQ) and echocardiography. Autonomic assessment included haemodynamic responses to standing, deep breathing and handgrip. Concomitant blood pressure variability (BPV) and heart rate variability (HRV) parameters were also derived. RESULTS: There were significant differences in all haemodynamic responses between SHF, HF-NEF and normal. Log transformed (ln) low frequency spectral component of BPV was lower in SHF (4.1 ± 0.3) than HF-NEF (4.2 ± 0.4) and normal (4.4 ± 0.1; p=0.001 SHF vs HF-NEF and vs normal). Ln LF/HF was greater in normal than HF-NEF and SHF (1.5 ± 0.7 vs 0.9 ± 1.0 vs 0.6 ± 0.6; p=0.003). Autonomic modulations correlated negatively with severity of heart failure. CONCLUSIONS: Autonomic responses in heart failure were blunted and the attenuation of responses correlated strongly with symptomatic and functional markers of disease severity. Autonomic dysfunction is a feature of the heart failure syndrome but is not dependent on ejection fraction.

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

AIMS: 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). METHODS AND RESULTS: 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). CONCLUSION: 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.

Hyponatraemia: A strong predictor of mortality in adults with congenital heart disease.

AIMS: We studied the prevalence of hyponatraemia and its prognostic implications in a large population of adult patients with congenital heart disease (ACHD). METHODS AND RESULTS: A total of 1004 ACHD patients were retrospectively entered in this study (mean age 36.2 +/- 14.4 years, 48.7% male). Cox regression was used to estimate mortality associated with hyponatraemia, adjusted for potential confounders using both multivariable regression and propensity score matching. Mean sodium concentration in this ACHD cohort was 137.6 +/- 2.6 mmol/L. The overall prevalence of hyponatraemia in this cohort was 15.5% and was highest in congenitally corrected transposition (33.3%), after Fontan operation (29.6%), and in patients with Eisenmenger syndrome (22.0%). Predictors of hyponatraemia were worse functional class, cyanosis, higher serum creatinine levels, and treatment with diuretics. Patients were followed for a median of 4.1 years, during which there were 96 deaths. Hyponatraemia was a strong predictor of death, independent of age, previous surgery, functional class, systemic ventricular function, creatinine levels, and the use of diuretics (adjusted HR 2.82, 95% CI: 1.72-4.63, P < 0.0001). CONCLUSION: Hyponatraemia is relatively common in ACHD. Hyponatraemia carries a three-fold higher risk of death in ACHD and is a simple, cheap but powerful marker of mortality.

Adaptive servo-ventilation in heart failure patients with sleep apnea: a real world study.

BACKGROUND: Congestive heart failure (CHF) patients often present with obstructive and central sleep apnea occurring concurrently within the same night. This study assessed the efficacy of, and improvements associated with, the use of adaptive servo-ventilation (ASV) in CHF patients with all types of sleep apnea. We hypothesized that ASV would be effective at reducing sleep apnea and improving both cardiac status and quality of life. METHODS: Eleven male patients with stable CHF and sleep apnea (apnea/hypopnea index (AHI) >15 events/h) were treated with 6 months optimized ASV and compared to 8 patients not receiving ASV. At baseline, both groups were comparable for New York Heart Association class, left ventricular ejection fraction (LVEF), plasma Brain Natriuretric Peptide (BNP) concentrations and AHI. All patients were receiving optimal medical therapy. RESULTS: At 6 months ASV significantly reduced AHI (mean (SD), baseline 49.0 (35.1) v ASV 7.6 (14.6); p=0.001) and LVEF was increased (median (inter-quartile range), treatment group: +5.7 (1.6-9.5) v comparison group: -4.0 (-8.9-+4.6)% respectively; p=0.04) but not BNP (p=0.59). The energy/vitality score of the SF-36 quality of life questionnaire was also improved at 6 months (treatment group: +10 (5-35) v comparison group: -12 (-18-+10); p=0.005). CONCLUSION: ASV effectively reduces all types of sleep apnea. Six months of use is associated with improvement in LVEF and aspects of quality of life.

Correlates of coronary angiography in patients with stable angina and geographical differences in its utilisation: the ACTION experience.

BACKGROUND: Utilisation of coronary angiography (CAG) varies between different countries. For patients with stable angina, the present study aimed to assess whether such differences could be explained by differences in patient characteristics, and whether these differences were related to outcome. METHODS: Using data from the ACTION trial, which compared long-acting nifedipine GITS with placebo in 7665 patients with stable angina from 19 countries, we determined by country the ratio of the observed (O) and the expected (E, based on multivariate models) number of patients who had a history of CAG before entry, or underwent CAG during a mean follow-up of 5 years. Similarly, we determined corresponding O/E ratios for the combined occurrence of any death, myocardial infarction (MI) or debilitating stroke (DS) during follow-up. RESULTS: O/E ratios for a history of CAG before entry ranged from 0.68 [95% confidence interval (CI) 0.60-0.77) for Sweden to 1.43 (95%CI 1.36-1.44) for Belgium, and were significantly correlated (p=0.04) to the corresponding O/E ratios for CAG during follow-up. The combined O/E ratio for CAG either before entry or during follow-up was not correlated (p=0.7) to the O/E for death, MI or DS, which ranged from 0.38 (95%CI undetermined) for Austria to 1.34 (95%CI 0.80-1.89) for France. CONCLUSIONS: The degree to which CAG is utilised in patients with stable angina varies between countries but is not related to the occurrence of death, MI or stroke. This supports the notion that percutaneous coronary intervention does not reduce the risk of events.

Ferric carboxymaltose in patients with heart failure and iron deficiency.

BACKGROUND: Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia. METHODS: We enrolled 459 patients with chronic heart failure of New York Heart Association (NYHA) functional class II or III, a left ventricular ejection fraction of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level <100 microg per liter or between 100 and 299 microg per liter, if the transferrin saturation was <20%), and a hemoglobin level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of intravenous iron (ferric carboxymaltose) or saline (placebo). The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at week 24. Secondary end points included the distance walked in 6 minutes and the health-related quality of life. RESULTS: Among the patients receiving ferric carboxymaltose, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% confidence interval [CI], 1.75 to 3.61). Among the patients assigned to ferric carboxymaltose, 47% had an NYHA functional class I or II at week 24, as compared with 30% of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups. CONCLUSIONS: Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile is acceptable. (ClinicalTrials.gov number, NCT00520780).

Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

BACKGROUND: Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. METHODS: This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259. FINDINGS: Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group. INTERPRETATION: Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit. FUNDING: Merck (USA).

Anemia in adults with congenital heart disease relates to adverse outcome.

OBJECTIVES: To assess the relation of anemia in noncyanotic adults with congenital heart disease (ACHD) to functional capacity and mortality. BACKGROUND: Anemia is common in acquired heart failure and affects prognosis. The presence of anemia and its relation to outcome in ACHD remain unknown. METHODS: Data were collected on consecutive noncyanotic ACHD patients attending our tertiary center between 2001 and 2006 in whom hemoglobin concentration was measured. Anemia was defined as hemoglobin concentration <13 g/dl in males and <12 g/dl in females. Cyanotic patients were excluded to avoid confounding from secondary erythrocytosis. RESULTS: Overall, 830 noncyanotic ACHD patients (age 36.5 +/- 15.0 years, 49.6% male) fulfilled the inclusion criteria. The prevalence of anemia was 13.1% and was highest in patients with congenitally corrected transposition of great arteries and Ebstein anomaly of the tricuspid valve. Anemic patients were more likely to be receiving diuretics (p < 0.0001) and have a lower mean corpuscular volume (p = 0.0001), with a trend toward a higher New York Heart Association functional class (p = 0.06). During a median follow-up of 47 months, 55 patients died. Anemic patients had a 3-fold higher mortality risk compared with nonanemic patients, even after propensity score adjustment for clinical variables such as systemic ventricular function, renal impairment, and diuretic therapy (adjusted hazard ratio: 3.00; 95% confidence interval: 1.46 to 6.13). CONCLUSIONS: Anemia is not uncommon in ACHD patients attending tertiary services and is associated with a 3-fold increased risk of death. Screening for anemia should be part of the routine assessment of ACHD patients for risk stratification and treatment when correctable causes are identified.

Rationale and design of Ferinject assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia.

AIMS: Iron deficiency (ID) and anaemia are common in patients with chronic heart failure (CHF). The presence of anaemia is associated with increased morbidity and mortality in CHF, and ID is a major reason for the development of anaemia. Preliminary studies using intravenous (i.v.) iron supplementation alone in patients with CHF and ID have shown improvements in symptom status. FAIR-HF (Clinical Trials.gov NCT00520780) was designed to determine the effect of i.v. iron repletion therapy using ferric carboxymaltose on self-reported patient global assessment (PGA) and New York Heart Association (NYHA) in patients with CHF and ID. METHODS AND RESULTS: This is a multi-centre, randomized, double-blind, placebo-controlled study recruiting ambulatory patients with symptomatic CHF with LVEF < or = 40% (NYHA II) or < or =45% (NYHA III), ID [ferritin <100 ng/mL or ferritin 100-300 ng/mL when transferrin saturation (TSAT) < 20%], and haemoglobin 9.5-13.5 g/dL. Patients were randomized in a 2:1 ratio to receive ferric carboxymaltose (Ferinject((R))) 200 mg iron i.v. or saline i.v. weekly until iron repletion (correction phase), then monthly until Week 24 (maintenance phase). Primary endpoints are (i) self-reported PGA at Week 24 and (ii) NYHA class at Week 24, adjusted for baseline NYHA class. CONCLUSION: This study will provide evidence on the efficacy and safety of iron repletion with ferric carboxymaltose in CHF patients with ID with and without anaemia.

Maximizing survival benefit with primary prevention implantable cardioverter-defibrillator therapy in a heart failure population.

BACKGROUND: Although implantable cardioverter-defibrillator (ICD) therapy reduces mortality in moderately symptomatic heart failure patients with an ejection fraction 20%), no benefit of ICD treatment was seen. Projected over each patient's predicted lifespan, ICD treatment added 6.3, 4.1, 3.0, 1.9, and 0.2 additional years of life in the lowest- to highest-risk groups, respectively. CONCLUSIONS: A clinical risk prediction model identified subsets of moderately symptomatic heart failure patients in SCD-HeFT in whom single-lead ICD therapy was of no benefit and other subsets in which benefit was substantial.

Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure).

OBJECTIVES: In this pre-specified subanalysis of the SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure) trial, which examined the effects of nebivolol in elderly heart failure (HF) patients, we explored the effects of left ventricular ejection fraction (EF) on outcomes, including the subgroups impaired EF (< or =35%) and preserved EF (>35%). BACKGROUND: Beta-blockers are established drugs in patients with HF and impaired EF, but their value in preserved EF is unclear. METHODS: We studied 2,111 patients; 1,359 (64%) had impaired (< or =35%) EF (mean 28.7%) and 752 (36%) had preserved (>35%) EF (mean 49.2%). The effect of nebivolol was investigated in these 2 groups, and it was compared to explore the interaction of EF with outcome. Follow-up was 21 months; the primary end point was all-cause mortality or cardiovascular hospitalizations. RESULTS: Patients with preserved EF were more often women (49.9% vs. 29.8%) and had less advanced HF, more hypertension, and fewer prior myocardial infarctions (all p < 0.001). During follow-up, the primary end point occurred in 465 patients (34.2%) with impaired EF and in 235 patients (31.2%) with preserved EF. The effect of nebivolol on the primary end point (hazard ratio [HR] of nebivolol vs. placebo) was 0.86 (95% confidence interval: 0.72 to 1.04) in patients with impaired EF and 0.81 (95% confidence interval: 0.63 to 1.04) in preserved EF (p = 0.720 for subgroup interaction). Effects on all secondary end points were similar between groups (HR for all-cause mortality 0.84 and 0.91, respectively), and no p value for interaction was <0.48. CONCLUSIONS: The effect of beta-blockade with nebivolol in elderly patients with HF in this study was similar in those with preserved and impaired EF.

Reduction in circulating testosterone relates to exercise capacity in men with chronic heart failure.

BACKGROUND: We investigated whether anabolic deficiency was linked to exercise intolerance in men with chronic heart failure (CHF). Anabolic hormones (testosterone, dehydroepiandrosterone sulfate, insulin-like growth factor 1 [IGF1]) contribute to exercise capacity in healthy men. This issue remains unclear in CHF. METHODS AND RESULTS: We studied 205 men with CHF (age 60 +/- 11 years, New York Heart Association [NYHA] Class I/II/III/IV: 37/95/65/8; LVEF [left ventricular ejection fraction]: 31 +/- 8%). Exercise capacity was expressed as peak oxygen consumption (peak VO(2)), peak O(2) pulse, and ventilatory response to exercise (VE-VCO(2) slope). In multivariable models, reduced peak VO(2) (and reduced peak O(2) pulse) was associated with diminished serum total testosterone (TT) (P < .01) and free testosterone (eFT; estimated from TT and sex hormone globulin levels) (P < .01), which was independent of NYHA Class, plasma N-terminal pro-brain natriuretic peptide, and age. These associations remained significant even after adjustment for an amount of leg lean tissue. In multivariable models, high VE-VCO(2) slope was related to reduced serum IGF1 (P < .05), advanced NYHA Class (P < .05), increased plasma NT-proBNP (P < .0001), and borderline low LVEF (P = .07). In 44 men, reassessed after 2.3 +/- 0.4 years, a reduction in peak VO(2) (and peak O(2) pulse) was accompanied by a decrease in TT (P < .01) and eFT (P