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.

Central and peripheral quadriceps fatigue in congestive heart failure.

AIMS: The clinical syndrome of heart failure includes exercise limitation that is not directly linked to measures of cardiac function. Quadriceps fatigability may be an important component of this and this may arise from peripheral or central factors. METHODS AND RESULTS: We studied 10 men with CHF and 10 healthy age-matched controls. Compared with a rest condition, 10 min after incremental maximal cycle exercise, twitch quadriceps force in response to supramaximal magnetic femoral nerve stimulation fell in both groups (CHF 14.1% ± 18.1%, p=0.037; CONTROL: 20.8 ± 11.0%, p<0.001; no significant difference between groups). There was no significant change in quadriceps maximum voluntary contraction voluntary force. The difference in the motor evoked potential (MEP) response to transcranial magnetic stimulation of the motor cortex between rest and exercise conditions at 10 min, normalised to the peripheral action potential, also fell significantly in both groups (CHF: 27.3 ± 38.7%, p=0.037; CONTROL: 41.1 ± 47.7%, p=0.024). However, the fall in MEP was sustained for a longer period in controls than in patients (p=0.048). CONCLUSIONS: The quadriceps is more susceptible to fatigue, with a similar fall in TwQ occurring in CHF patients at lower levels of exercise. This is associated with no change in voluntary activation but a lesser degree of depression of quadriceps motor evoked potential.

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.

Prevalence and outcome of subclinical rheumatic heart disease in India: the RHEUMATIC (Rheumatic Heart Echo Utilisation and Monitoring Actuarial Trends in Indian Children) study.

OBJECTIVE: To study the prevalence and medium term outcome of subclinical rheumatic heart disease (RHD) in India. DESIGN: Cross sectional echocardiographic screening study. SETTING: School children aged 5-15 years living in rural areas of north India. PATIENTS: A cross sectional echocardiographic screening study was carried out among 6270 randomly selected school children aged 5-15 years (10.8 ± 2.6 years; 52.7% male). Of all the abnormal cases, 100 children (78%) were restudied at a mean follow-up of 15.4 ± 6.6 months. INTERVENTION: Echocardiographic screening. MAIN OUTCOME MEASURE: Echocardiography-Doppler criteria based prevalence of RHD. RESULTS: Clinical examination detected mitral regurgitation in five patients and the estimated prevalence of clinical RHD was 0.8/1000 school children. Echocardiography-Doppler diagnosed RHD in 128 cases, giving a prevalence of 20.4/1000 school children (95% CI 16.9 to 23.9/1000 children). On multivariate analysis, older age (OR 1.93, 95% CI 1.29 to 2.88; p = 0.001), female sex (OR 1.84, 95% CI 1.25 to 2.72; p = 0.002) and government funded school student, which is a surrogate measure of lower socioeconomic status (OR 1.55, 95% CI 1.02 to 2.34; p = 0.039) were found to be independent predictors of RHD. On follow up, the severity of subclinical RHD was non-progressive in 68 children (68%) while it worsened in four (4%) and regressed in 28 children (28%). CONCLUSIONS: The prevalence of RHD is several fold higher using echocardiographic screening compared with clinical examination. The prevalence is higher among girls and children of lower socioeconomic status. In the majority of cases, subclinical RHD appears to be non-progressive on medium term follow up. Routine echocardiographic screening may be indicated in populations at high risk of RHD.

Role of cardiovascular magnetic resonance as a gatekeeper to invasive coronary angiography in patients presenting with heart failure of unknown etiology.

BACKGROUND: In patients presenting with new-onset heart failure of uncertain etiology, the role of coronary angiography (CA) is unclear. Although conventionally performed to differentiate underlying coronary artery disease from dilated cardiomyopathy, CA is associated with a risk of complications and may not detect an ischemic cause resulting from arterial recanalization or an embolic episode. In this study, we assessed the diagnostic accuracy of a cardiovascular magnetic resonance (CMR) protocol incorporating late gadolinium enhancement (LGE) and magnetic resonance CA as a noninvasive gatekeeper to CA in determining the etiology of heart failure in this subset of patients. METHODS AND RESULTS: One hundred twenty consecutive patients underwent CMR and CA. The etiology was ascribed by a consensus panel that used the results of the CMR scans. Similarly, a separate consensus group ascribed an underlying cause by using the results of CA. The diagnostic accuracy of both strategies was compared against a gold-standard panel that made a definitive judgment by reviewing all clinical data. The study was powered to show noninferiority between the 2 techniques. The sensitivity of 100%, specificity of 96%, and diagnostic accuracy of 97% for LGE-CMR were equivalent to CA (sensitivity, 93%; specificity, 96%; and diagnostic accuracy, 95%). As a gatekeeper to CA, LGE-CMR was also found to be a cheaper diagnostic strategy in a decision tree model when United Kingdom-based costs were assumed. The economic merits of this model would change, depending on the relative costs of LGE-CMR and CA in any specific healthcare system. CONCLUSION: This study showed that LGE-CMR is a safe, clinically effective, and potentially economical gatekeeper to CA in patients presenting with heart failure of uncertain etiology.

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.

Predictors of clinical outcomes in elderly patients with heart failure.

AIMS: Heart failure (HF) in the elderly carries a poor prognosis. We used the SENIORS dataset of elderly HF patients aged ≥70 years in order to develop a risk model for this population. METHODS AND RESULTS: The SENIORS trial evaluated the effects of nebivolol and enrolled 2128 patients ≥70 years with HF (ejection fraction ≤35%, or recent HF admission). We randomly selected 1400 patients from the full dataset to produce a derivation cohort and the remaining 728 patients were used as a validation cohort. Baseline variables were entered into a bootstrap model with 200 iterations to determine their association with two outcomes, the composite of all-cause mortality or cardiovascular hospitalization, or all-cause mortality alone. Variables retaining a significant association with these outcomes in a multivariate model were used to develop a risk prediction score tested in the validation cohort. Five factors were associated with increased risk of both outcomes in the multivariate model: higher New York Heart Association class, higher uric acid level, lower body mass index, prior myocardial infarction, and larger left atrial (LA) dimension. For the composite outcome, peripheral arterial disease, years with heart failure, right bundle branch block, diabetes mellitus, and orthopnoea were also retained. For all-cause mortality, creatinine, 6 min walk test distance, coronary artery disease, and age were retained. CONCLUSION: In addition to conventional prognostic markers, uric acid and LA dimension appear to be important novel risk prediction markers in elderly patients with heart failure, and could be useful in guiding management.

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.

Gender differences in cardiac remodeling and clinical outcomes in chronic stable angina pectoris (from the ACTION Trial).

Our objective was to determine the gender differences in the relation between the echocardiographic parameters of cardiac remodeling and clinical outcomes in patients with chronic stable angina. The baseline ejection fraction (EF), end-diastolic volume, and end-systolic volume were assessed in 7,016 patients in the study "A Coronary disease Trial Investigating Outcomes with Nifedipine gastrointestinal therapeutic system" (ACTION). All-cause and cardiac mortality and incident heart failure were determined after a median of 5.0 years. Cox proportional hazard models were fit to determine the effect of gender on the relation between the echocardiographic parameters and clinical outcomes (interaction p <0.10). The association between the EF and mortality differed significantly between men and women, with women demonstrating a marked increase in risk as the EF decreased, compared to men (interaction p = 0.03, adjusted p = 0.07). Also, a significant interaction by gender was seen for the association between the end-systolic volume and the risk of heart failure (interaction p = 0.01, adjusted p = 0.05). In conclusion, the relation between EF and mortality differed according to gender in patients with chronic coronary disease, with women having a greater risk of adverse outcomes as the EF decreased. Similar findings were observed with the end-systolic and end-diastolic volumes and the risk of heart failure. These findings may reflect inherent gender-based differences in ischemic heart disease and cardiac remodeling and might help to identify women at high risk.

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.

Effects of carvedilol or metoprolol on PAI-1, tPA-mass concentration or Von Willebrand factor in chronic heart failure--a COMET substudy.

INTRODUCTION: In COMET (Carvedilol or Metoprolol European Trial), carvedilol reduced mortality compared with metoprolol in patients with chronic heart failure. We hypothesized that carvedilol might have greater effects on endothelial derived haemostatic factors than metoprolol. We aimed to study the effects of carvedilol or metoprolol on tissue plasminogen activator (tPA), its inhibitor PAI-1 and Von Willebrand factor (VWF) in patients with heart failure. MATERIAL AND METHODS: We recruited 260 patients (134 on carvedilol, 126 on metoprolol), mean age 66 years and 84% of them men. Plasma mass concentrations of tPA and PAI-1and percent of VWF were measured at baseline and after one and two years of treatment. RESULTS: Plasma tPA, PAI-1 and VWF were similar between treatment groups at baseline and no significant differences between groups emerged after one or two years of treatment. In paired analyses in patients assigned to carvedilol, median PAI-1 level decreased from 37.2 to 32.1 microg/l at two years (p=0.034) and of VWF decreased from baseline to one year (240 vs. 218%, p=0.023) in patients assigned to carvedilol but were not reduced at any time in patients assigned to metoprolol. Plasma tPA increased over time in both treatment groups (p=0.013 and 0.027 respectively). CONCLUSION: We found no significant difference in the effects of carvedilol or metoprolol on tPA, PAI-1 and VWF. Comparison over time within treatment groups suggested that PAI-1 and VWF might have declined on carvedilol but not on metoprolol. Our hypothesis is not proved but this may reflect an inadequate sample size rather than lack of an effect.

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.