Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure.

BACKGROUND: Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES: This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). METHODS: Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm. RESULTS: Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m2; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m2, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m2. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m2 lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m2 (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m2 (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m2) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR. CONCLUSIONS: Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction.

Limited Added Value of Circulating Inflammatory Biomarkers in Chronic Heart Failure.

OBJECTIVES: This study sought to evaluate whether a panel of biomarkers improved prognostication in patients with heart failure (HF) and reduced ejection fraction of ischemic origin using a systematized approach according to suggested requirements for validation of new biomarkers. BACKGROUND: Modeling combinations of multiple circulating markers could potentially identify patients with HF at particularly high risk and aid in the selection of individualized therapy. METHODS: From a panel of 20 inflammatory and extracellular matrix biomarkers, 2 different biomarker panels were created and added to the Seattle HF score and the prognostic model from the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study (n = 1,497), which included conventional clinical characteristics and C-reactive protein and N-terminal pro-B-type natriuretic peptide. Interactions with statin treatment were also assessed. RESULTS: The two models-model 1 (endostatin, interleukin 8, soluble ST2, troponin T, galectin 3, and chemokine [C-C motif] ligand 21) and model 2 (troponin T, soluble ST2, galectin 3, pentraxin 3, and soluble tumor necrosis factor receptor 2)-significantly improved the CORONA and Seattle HF models but added only modestly to their Harrell's C statistic and net reclassification index. In addition, rosuvastatin had no effect on the levels of a wide range of inflammatory and extracellular matrix markers, but there was a tendency for patients with a lower level of biomarkers in the 2 panels to have a positive effect from statin treatment. CONCLUSIONS: In the specific HF patient population studied, a multimarker approach using the particular panel of biomarkers measured was of limited clinical value for identifying future risk of adverse outcomes.

Inflammatory cytokines in chronic heart failure: interleukin-8 is associated with adverse outcome. Results from CORONA.

AIM: We investigated the ability of prototypical inflammatory cytokines to predict clinical outcomes in a large population of patients with chronic systolic heart failure (HF). METHODS AND RESULTS: Serum levels of tumour necrosis factor-α (TNF-α), soluble TNF receptors type I and II (sTNF-RI and sTNF-RII), and the chemokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) were analysed in 1464 patients with chronic ischaemic systolic HF in the CORONA study, aged ≥ 60 years, in NYHA class II-IV, and related to the primary endpoint (n = 320), as well as any coronary event (n = 255), all-cause mortality (n = 329), cardiovascular (CV) mortality (n = 268), and the composite endpoint hospitalization from worsening heart failure (WHF) or CV mortality (n = 547). TNF-α, sTNF-RI, sTNF-RII, and IL-8, but not MCP-1, were independent predictors of all endpoints except the coronary endpoint in multivariable models including conventional clinical variables. After further adjustment for estimated glomerular filtration rate, the ApoB/ApoA-1 ratio, NT-proBNP, and high-sensitivity C-reactive protein, only IL-8 remained a significant predictor of all endpoints (except the coronary endpoint), while sTNF- RI remained independently associated with CV mortality. Adding IL-8 to the full model led to a significant improvement in net reclassification for all-cause mortality and CV hospitalization, but only a borderline significant improvement for the primary endpoint, CV mortality, and the composite endpoint WHF hospitalization or CV mortality. CONCLUSION: Our study supports a relationship between IL-8 and outcomes in patients with chronic HF. However, the clinical usefulness of IL-8 as a biomarker in an unselected HF population is at present unclear.

Osteoprotegerin predicts progression of chronic heart failure: results from CORONA.

BACKGROUND: Osteoprotegerin (OPG) may be implicated in the pathogenesis of heart failure (HF), and circulating levels predict survival in patients with postinfarction HF. Our primary goal was to determine whether OPG provided independent prognostic information in patients with chronic HF, and to examine its potential interactions with statin therapy. METHODS AND RESULTS: OPG as a risk factor for the primary end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke; n=318), all-cause mortality (n=329), and all-cause mortality/hospitalization for worsening of heart failure (WHF; n=475) was investigated in 1464 patients (≥60 years, New York Heart Association class II to IV, ischemic systolic HF, optimal pharmacological therapy) in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo. In multivariate analyses, OPG (continuous variable) added no significant predictive information for risk estimation of the primary end point (adjusting for left ventricular ejection fraction, New York Heart Association class, age, body mass index, diabetes, sex, intermittent claudication, heart rate, serum creatinine, apoA1, and N-terminal pro-B-type natriuretic peptide). However, OPG added independent predictive information for WHF hospitalization (hazard ratio [HR] 1.10 [1.04 to 1.16], P<0.001) and all-cause mortality/WHF hospitalization (HR 1.06 [1.01 to 1.11]). The HR indicated a reduced risk for all-cause mortality in the rosuvastatin group in those with lowest OPG values (tertile 1, HR=0.66 unadjusted [P=0.025]; HR=0.71 Cox adjusted [P=0.025]; interaction by treatment effect for the tertiles P=0.086). CONCLUSIONS: OPG added no predictive information for the primary end point, but independently predicted WHF hospitalization in older patients with advanced chronic systolic HF of ischemic etiology. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

C-reactive protein and tumor necrosis factor-alpha in relation to insulin-mediated glucose uptake, smoking and atherosclerosis.

OBJECTIVES: To examine the hypothesis that serum concentration of C-reactive protein (CRP) is inversely associated with insulin sensitivity and obesity, and that this may by mediated by tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6). MATERIAL AND METHODS: Cross-sectional, one-center study of a population-based sample of 58-year-old Swedish men (n = 98). Exclusion criteria were cardiovascular disease, clinical diabetes mellitus and/ or continuous cardiovascular medication. Glucose infusion-rate (euglycemic hyperinsulinemic clamp), adjusted for fat-free mass, which together with total body fat was measured by dual-energy X-ray absorptiometry. Serum concentrations of CRP, TNFalpha, soluble TNFalpha receptor 2 (sTNFAR2), IL-6 determined by ELISA. Ultrasound was used to measure intima-media thickness (IMT) in both common carotid arteries, carotid bulbs and in the right femoral artery. RESULTS: CRP was inversely associated with insulin sensitivity (r = -0.28, p < 0.01) and with total body fat (r = 0.31, p < 0.01), but not independently of the TNFalpha and sTNFAR2 product. Serum CRP, TNFalpha, sTNFAR2, but not IL-6, were associated with low insulin sensitivity, total body fat, abdominal obesity, hyperinsulinemia, hypertriglyceridemia, low HDL cholesterol and small LDL particles, i.e. the metabolic syndrome. These associations were independent of smoking and carotid and femoral artery IMT. CONCLUSIONS: Serum concentrations of CRP were related to insulin sensitivity and accompanying factors constituting the metabolic syndrome. The results indicate that this association may be mediated by adipose tissue and TNFalpha effects, the latter measured as the product of TNFalpha and sTNFAR2. This was a cross-sectional study and causality cannot be proven.

Circulating estradiol is an independent predictor of progression of carotid artery intima-media thickness in middle-aged men.

CONTEXT: Estrogen treatment of men with prostate cancer is associated with increased cardiovascular morbidity and mortality; however, the role of endogenous estrogen levels for atherosclerotic disease in men is unknown. OBJECTIVE: The objective of the study was to determine whether endogenous serum estradiol (E2) levels predict the progression of carotid artery intima-media thickness in men. DESIGN, SETTING AND PARTICIPANTS: This was a population-based, prospective cohort study (the Atherosclerosis and Insulin Resistance study) conducted in Göteborg, Sweden, among 313 Caucasian men without cardiovascular or other clinically overt diseases. Carotid artery intima-media thickness, an index of preclinical atherosclerosis, was measured by ultrasound at baseline (58 yr of age) and after 3 yr of follow-up. Serum sex hormone levels and cardiovascular risk factors (body mass index, waist to hip ratio, systolic blood pressure, serum triglycerides, plasma c-peptide, and smoking status) were assessed at study entry. INTERVENTION: There was no intervention. MAIN OUTCOME MEASURES: Association between baseline total and free E2 levels and progression of carotid intima-media thickness over 3 yr with adjustments for cardiovascular risk factors was measured. RESULTS: In univariate analyses, both total and free E2 levels at baseline were positively associated with the annual change in intima-media thickness. In linear regression models including E2 and cardiovascular risk factors, low-density lipoprotein and high-density lipoprotein cholesterol and E2 were identified as independent predictors of progression of carotid artery intima-media thickness (total E2 beta = 0.187, P = 0.001; and free E2 beta = 0.183, P = 0.003). CONCLUSIONS: Circulating E2 is a predictor of progression of carotid artery intima-media thickness in middle-aged men. Further studies are needed to investigate the role of endogenous E2 for incident cardiovascular disease events.

Prevalence of diabetes and impaired glucose tolerance in 64-year-old Swedish women: experiences of using repeated oral glucose tolerance tests.

OBJECTIVE: The purpose of this study was to describe the prevalence of diabetes and impaired glucose tolerance (IGT) in middle-aged women and to examine the variability and practical use of the oral glucose tolerance test (OGTT) in the screening for IGT and diabetes. RESEARCH DESIGN AND METHODS: All 64-year-old women living in Göteborg, Sweden, were invited to take part in a screening examination (n = 4,856). Of these, 82% (n = 3,998) responded and 53% (n = 2,595) participated and underwent anthropometric measurements and a 75-g standardized OGTT that was repeated within 2 weeks in those not showing normal glucose tolerance (NGT). RESULTS: The prevalences of known and new diabetes, IGT at both OGTTs, and impaired fasting glucose were 4.7, 4.8, 14.4, and 6.4%, respectively. Half of the women with diabetes were previously undiagnosed, and 37% of the diagnoses were based on OGTT and diabetes 2-h values at both or one of the two examinations. Women with IGT at both OGTTs, in comparison with those with one impaired and one normal OGTT, had higher BMI, waist girth, and blood pressure. More than 40% of the women showed impaired glucose metabolism. CONCLUSIONS: Among these women, the prevalence of undetected diabetes was high and repeated OGTTs were needed to identify and not misclassify a considerable proportion of patients. The degree of glucose tolerance impairment and the number of abnormal OGTTs were directly associated with occurrence of components of the metabolic syndrome.

A statin in the treatment of heart failure? Controlled rosuvastatin multinational study in heart failure (CORONA): study design and baseline characteristics.

BACKGROUND: Previous prospective outcome studies of statins have not provided any guidance on benefit-risk in patients with heart failure. AIM: The primary objective is to determine whether rosuvastatin (10 mg) reduces the combined endpoint of cardiovascular mortality, non-fatal myocardial infarction or non-fatal stroke (time to first event). The first secondary endpoint is all-cause mortality. METHODS: CORONA is a randomized, double-blind, placebo-controlled trial. Briefly, men and women, aged > or =60 years with chronic symptomatic systolic heart failure of ischemic aetiology and ejection fraction < or =0.40 (NYHA class III and IV) or < or =0.35 (NYHA class II) were eligible if they were not using or in need of cholesterol lowering drugs. RESULTS: Mean age was 73 years (n=5016; 24% women), with 37% in NYHA II and 62% in NYHA III, ejection fraction 0.31, total cholesterol 5.2 mmol/L. Sixty percent have a history of myocardial infarction, 63% hypertension, and 30% diabetes. Patients are well treated for heart failure with 90% on loop or thiazide diuretics, 42% aldosterone antagonists, 91% ACE inhibitor or AT-I blocker, 75% beta-blockers, and 32% digitalis. CONCLUSION: CORONA is important for three main reasons: (1) A positive result is very important because of the high risk of the population studied, the increasing prevalence of elderly patients with chronic symptomatic systolic heart failure in our society, and the health economic issues involved. (2) If negative, new mechanistic questions about heart failure have to be raised. (3) If neutral we can avoid unnecessary polypharmacy.

Apolipoprotein B/apolipoprotein A-I in relation to the metabolic syndrome and change in carotid artery intima-media thickness during 3 years in middle-aged men.

BACKGROUND AND PURPOSE: The apolipoprotein B (apoB)/apolipoprotein A-I (apoA-I) ratio is a measure of the relationship between different lipoprotein particles and a powerful predictor of coronary death. The aim was to examine whether apoB/apoA-I was associated with the metabolic syndrome (MetS) at baseline and also with the future change in carotid artery intima-media thickness (IMT). METHODS: In 313 58-year-old men, carotid artery IMT was measured bilaterally by high-resolution B-mode ultrasound at baseline and after 3 years of follow-up. Serum apolipoprotein concentrations and the components of MetS were measured at study entry. RESULTS: ApoB/apoA-I showed statistically significant associations with body mass index, waist-to-hip ratio, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein (LDL) particle size, insulin, and diastolic blood pressure. Two thirds of the patients with MetS had high apoB/apoA-I ratios (>0.90) compared with one third of those without the syndrome (P<0.001). The IMT change was associated with apoB, total cholesterol, LDL cholesterol, triglycerides, and inversely with HDL cholesterol and LDL particle size at entry, and there was a strong colinearity between these variables. The subjects with apoB/apoA-I above the first tertile (0.74) had a 20-microm-higher (95% CI, 7 to 33) annual increase in IMT compared with those below this level after adjustment for blood pressure and smoking. CONCLUSIONS: The apoB/apoA-I ratio was strongly associated with MetS and its components at baseline. ApoB/apoA-I at baseline was related to the change in carotid artery IMT during 3 years of follow-up. There was a strong colinearity between apoB/apoA and the atherogenic lipids.

Metoprolol CR/XL in postmyocardial infarction patients with chronic heart failure: experiences from MERIT-HF.

BACKGROUND: The benefit of beta-blockers post-myocardial infarction (MI) was established in the late 1970s. Major advances in the treatment of MI have since occurred. However, patients with chronic heart failure (CHF) were excluded from those trials. The purpose of this study was to assess the effect of beta-blockers in post-MI patients with CHF receiving contemporary management. METHODS: This was a prespecified subgroup analysis of a double-blind, randomized trial: the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF). Patients with CHF in New York Heart Association class II to IV with an ejection fraction (EF) < or =0.40 and a history of being hospitalized for an acute MI (n = 1926) were randomized to metoprolol succinate controlled release/extended release (CR/XL) versus placebo. Mean EF was 0.28, and the mean follow-up was 1 year. RESULTS: Metoprolol CR/XL reduced total mortality by 40% (95% CI 0.20-0.55, P =.0004), and sudden death by 50% (95% CI 0.26-0.66, P =.0004). The combined end point of all-cause mortality/hospitalization for worsening CHF was reduced by 31% (95% CI 0.16-0.44, P <.0001), and cardiac death/nonfatal acute MI by 45% (95% CI 0.26-0.58, P <.0001). A post-hoc analysis showed that the outcome in patients with earlier revascularization (44%) and outcome in those with more severe CHF (20%) was similar to the entire post-MI population. CONCLUSIONS: In post-MI patients with symptomatic CHF, beta-blockade continues to exert a profound reduction in mortality and morbidity in the presence of contemporary management that includes early and late revascularization, angiotensin-converting enzyme inhibitors, aspirin, and statins.

Intima-media thickness in cardiovascularly asymptomatic hypopituitary adults with growth hormone deficiency: relation to body mass index, gender, and other cardiovascular risk factors.

OBJECTIVE: Increased cardiovascular mortality and carotid atherosclerosis have been observed in hypopituitary patients with untreated GH deficiency (GHD), but results are contradictory and relations to cardiovascular risk factors are not clear. The aim of this study was to investigate intima-media thickness (IMT) in relation to cardiovascular risk factors in adults with GHD. DESIGN: Cross-sectional observational study of 21 men and 13 women with GHD, but without cardiovascular disease, compared to two healthy control groups matched for age, sex and smoking habits. One control group was matched for body mass index (BMI) and the other group was nonobese. MEASUREMENTS: IMT of the carotid and femoral arteries, blood pressure, blood samples and anthropometric data. RESULTS: Patients had 12% thicker composite carotid IMT [(IMT of common carotid artery + IMT of bulb)/2] compared to nonobese controls (P = 0.022), but IMT was not different compared to BMI-matched controls. Femoral IMT did not differ between patients and controls. Patients had higher waist : hip ratio (WHR), heart rate, serum triglycerides and fasting insulin concentrations in combination with lower high-density lipoprotein (HDL) cholesterol and smaller low-density lipoprotein (LDL) peak particle size compared to both nonobese and to BMI-matched controls. This cardiovascular risk pattern was more pronounced in female patients than in male patients compared to their gender controls. Carotid IMT was related to age, serum cholesterol, LDL cholesterol and smoking in the patient group. Only age was independently related to carotid IMT in multivariate analysis. CONCLUSIONS: These results indicate that high BMI in GH-deficient patients contribute to their increased intima-media thickness. However, several cardiovascular risk factors are present in this patient group independent of their increased BMI, especially in women.

Circulating ICAM-1 (intercellular cell-adhesion molecule 1) is associated with early stages of atherosclerosis development and with inflammatory cytokines in healthy 58-year-old men: the Atherosclerosis and Insulin Resistance (AIR) study.

There is a lack of data on circulating levels of cell-adhesion molecules in relation to subclinical atherosclerosis measured in both the carotid and femoral arteries in humans. The aim of the present study was to investigate the relationship between clinically silent atherosclerosis and cell-adhesion molecules, and to explore the relationship between these molecules, C-reactive protein and the inflammatory cytokines interleukin-6, tumour necrosis factor-alpha (TNF-alpha), soluble TNF-alpha receptor p55 and soluble TNF-alpha receptor p75. The study group (n=391) consisted of clinically healthy 58-year-old men recruited from the general population. The results showed a positive trend between levels of soluble intercellular cell-adhesion molecule 1 (sICAM-1) and plaque occurrence in the carotid and femoral arteries (P=0.008), and also a univariate correlation between sICAM-1 levels and the composite variable of carotid and femoral intima-media thickness (P<0.001). When adjusted for other risk factors, the relationship between sICAM-1 and intima-media thickness no longer reached statistical significance. The level of sICAM-1 was associated with those of the pro-inflammatory cytokine TNF-alpha, its two soluble receptors, and also interleukin-6 and C-reactive protein. Levels of soluble E-selectin and vascular cell-adhesion molecule 1 (VCAM-1) showed weak or no association with subclinical atherosclerosis and inflammatory variables. Thus, in clinically healthy middle-aged men, levels of sICAM-1, but not of soluble VCAM-1 or E-selectin, were associated with both subclinical atherosclerosis and inflammatory variables.