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.

Atherosclerotic lesions in lymphoma survivors treated with radiotherapy.

BACKGROUND AND PURPOSE: Radiotherapy causes premature atherosclerosis in Hodgkin's lymphoma survivors (HLSs). We determined whether atherosclerosis within the radiation field was predicted by traditional risk factors independent of radiation and compared the extent of atherosclerosis in HLSs treated with mantle field radiotherapy with non-irradiated patients. MATERIAL AND METHODS: Forty-three HLSs (median age 50 years, range 38-63) treated with mantle field radiotherapy were included. Cardiovascular risk factors were registered at first follow-up (FU-1) 5-13 years after treatment. A second follow-up (FU-2) occurred 18-27 years after treatment. At FU-2, in-field atherosclerosis was assessed by computed tomography with calculation of coronary artery calcium volume score (CACS) and pre-cranial artery atherosclerosis score (PAS). Peripheral endothelial dysfunction was assessed by ante-brachial strain-gauge plethysmography. CT angiography of pre-cranial vessels was also performed in 43 non-irradiated patients. RESULTS: Multiple linear regression analyses showed that cholesterol at FU-1 was a predictor of CACS (ß 308 (95% CI 213-403), p < 0.001), PAS (ß 3.67 (95% CI 2.29-5.04), p < 0.001) and peripheral endothelial dysfunction (ß 2.74 (95% CI 0.47-5.01), p = 0.02). There were more atherosclerotic lesions in HLSs (n = 141) than in non-irradiated patients (n = 73, p = 0.001). CONCLUSION: Irradiated arteries are characterized by widespread atherosclerotic lesions aggravated by elevated levels of cholesterol.

Soluble glycoprotein 130 predicts fatal outcomes in chronic heart failure: analysis from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).

BACKGROUND: Glycoprotein 130 (gp130) is the common signal-transducing receptor subunit of the interleukin-6 (IL-6) family, which may be involved in the progression of heart failure (HF). We hypothesized that soluble gp130 would provide prognostic information beyond that of IL-6 in a population with HF from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). METHODS AND RESULTS: The associations of soluble gp130 and IL-6 with morbidity, mortality, and mode of death were assessed by immunoassays in a subset of 1452 patients enrolled in the CORONA trial, which included patients with HF, aged ≥60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. In multivariable analyses, including C-reactive protein, IL-6, troponin T, and N-terminal pro-B-type natriuretic peptide, elevated soluble gp130 (fifth quintile versus all lower quintiles) was associated with all-cause mortality (hazard ratio, 1.47 [1.11-1.93]; P=0.006), cardiovascular mortality (hazard ratio, 1.38 [1.01-1.87]; P=0.042), and death from worsening HF (hazard ratio, 1.85 [1.09-3.14]; P=0.002), but not with the primary end point (composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke; hazard ratio, 1.12 [0.84-1.50]; P=0.44). Plasma IL-6 was not associated with outcomes in multivariable analyses. CONCLUSIONS: Marked elevations in soluble gp130 are associated with total and cardiovascular mortality, as well as deaths from worsening HF, in elderly patients with HF of ischemic cause CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).

Cardiovascular disease (CVD) due to atherosclerosis of the arterial vessel wall and to thrombosis is the foremost cause of premature mortality and of disability-adjusted life years (DALYs) in Europe, and is also increasingly common in developing countries.1 In the European Union, the economic cost of CVD represents annually E192 billion1 in direct and indirect healthcare costs. The main clinical entities are coronary artery disease (CAD), ischaemic stroke, and peripheral arterial disease (PAD). The causes of these CVDs are multifactorial. Some of these factors relate to lifestyles, such as tobacco smoking, lack of physical activity, and dietary habits, and are thus modifiable. Other risk factors are also modifiable, such as elevated blood pressure, type 2 diabetes, and dyslipidaemias, or non-modifiable, such as age and male gender. These guidelines deal with the management of dyslipidaemias as an essential and integral part of CVD prevention. Prevention and treatment of dyslipidaemias should always be considered within the broader framework of CVD prevention, which is addressed in guidelines of the Joint European Societies' Task forces on CVD prevention in clinical practice.2 ­ 5 The latest version of these guidelines was published in 20075; an update will become available in 2012. These Joint ESC/European Atherosclerosis Society (EAS) guidelines on the management of dyslipidaemias are complementary to the guidelines on CVD prevention in clinical practice and address not only physicians [e.g. general practitioners (GPs) and cardiologists] interested in CVD prevention, but also specialists from lipid clinics or metabolic units who are dealing with dyslipidaemias that are more difficult to classify and treat.

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.

Relation of coronary artery calcium score to premature coronary artery disease in survivors >15 years of Hodgkin's lymphoma.

Long-term survival in Hodgkin lymphoma (HL) survivors is complicated by an increased risk for coronary artery disease (CAD) due to radiation-induced endothelial damage. Our objective was to quantify total coronary artery calcium (CAC) in long-term HL survivors who had survived >or=15 years after treatment and relate it to the presence of verified CAD. Forty-seven HL survivors 50 +/- 7 years of age who had survived 22 +/- 3 years after mediastinal radiotherapy underwent CAC scoring (Agatston and volume scores) in a multidetector computed tomographic scanner. Total volume score was higher in 7 patients (15%) with verified CAD (median 439, range 8 to 2,057) compared to those without (median 68, 0 to 767, p = 0.022). Ten patients had CAC scores >200. Of these 10, 5 had undergone revascularization of coronary arteries. None of the 8 patients with a CAC score 0 had symptomatic CAD. In conclusion, postirradiation CAC can be quantified by CAC score and this may be a simple and suitable method to screen for CAD in long-term HL survivors. Patients with a CAC score >200 often have clinically significant CAD, and further investigation including angiography may be justified. Lower CAC scores, however, do not exclude CAD and further studies should be undertaken to define the best algorithm for follow-up of this patient group.

Prevalence, incidence, and prognostic value of anaemia in patients after an acute myocardial infarction: data from the OPTIMAAL trial.

AIMS: The prevalence, incidence, and prognostic value of anaemia in patients with an acute myocardial infarction (AMI) complicated by heart failure is unclear. METHODS AND RESULTS: We analysed the relationship between haemoglobin (Hb) and outcome in 5010 patients with AMI complicated by heart failure in the OPTIMAAL study. In 3921 patients, follow-up Hb levels were available at 365 (+/-90) days. In a subgroup of 224 patients, iron-related haematinics were assessed at baseline and during follow-up. At baseline, mean Hb was 12.6 +/- 1.3 g/dL in women and 13.7 +/- 1.4 g/dL in men. Hb < 11.5 g/dL was found in 9.3% of patients (women: 18.2%, men: 5.8%). Lower haemoglobin at baseline was clearly associated with female gender and the presence of diabetes, higher age and Killip class, lower body mass index, systolic blood pressure, total cholesterol, and the absence of current smoking (all P < 0.05). Higher Hb [per one standard deviation (SD)] related to lower mortality [adjusted hazard ratios (HR) 0.88; 95% confidence interval (CI) 0.83-0.93], CHF hospitalizations [HR 0.85 (0.77-0.93)], and all-cause hospitalizations [HR 0.96 (0.92-0.99), all P < 0.05]. In patients without anaemia at baseline, the anaemia incidence after 1 year of follow-up was 10.1% in women and 10.0% in men. Of patients with anaemia at baseline, 65% did not have anaemia at 12 months and 46% did not have anaemia at any time during follow-up (median 3.0 years, inter-quartile range, Q1-Q3 = 2.7-3.3 years). At 12 months, an increase in Hb (per SD) was related to lower mortality [HR 0.73 (0.63-0.85; P < 0.0001)] independent of baseline Hb and other clinical characteristics. CONCLUSION: In patients with complicated AMIs, anaemia on admission and/or reductions in haemoglobin during follow-up are independent risk factors for mortality and hospitalization. Studies are warranted to determine whether correcting anaemia after a complicated AMI improves outcome.

Increased systemic and myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and experimental heart failure.

AIMS: Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin-2) is a glycoprotein with bacteriostatic properties. Growing evidence suggests that NGAL may also be involved in cell survival, inflammation, and matrix degradation. We therefore aimed to investigate the role of NGAL in heart failure (HF). METHODS AND RESULTS: Our main findings were (i) patients with acute post-myocardial infarction (MI) HF (n = 236) and chronic HF (n = 150) had elevated serum levels of NGAL (determined by enzyme immunoassay), significantly correlated with clinical and neurohormonal deterioration, (ii) in patients with HF following acute MI, elevated NGAL levels of at baseline were associated with adverse outcomes (median of 27 months follow-up), (iii) in a rat model of post-MI HF, NGAL/lipocalin-2 gene expression was increased in the non-ischaemic part of the left ventricle primarily located to cardiomyocytes, (iv) strong NGAL immunostaining was found in cardiomyocytes within the failing myocardium both in experimental and clinical HF, (v) interleukin-1beta and agonists for toll-like receptors 2 and 4, representing components of the innate immune system, were potent inducers of NGAL/lipocalin-2 in isolated neonatal cardiomyocytes. CONCLUSION: Our demonstration of enhanced systemic and myocardial NGAL expression in clinical and experimental HF further support a role for innate immune responses in the pathogenesis of HF.

Enhanced expression of the homeostatic chemokines CCL19 and CCL21 in clinical and experimental atherosclerosis: possible pathogenic role in plaque destabilization.

OBJECTIVE: Based on their role in T-cell homing into nonlymphoid tissue, we examined the role of the homeostatic chemokines CCL19 and CCL21 and their common receptor CCR7 in coronary artery disease (CAD). METHODS AND RESULTS: We performed studies in patients with stable (n=40) and unstable (n=40) angina and healthy controls (n=20), in vitro studies in T-cells and macrophages, and studies in apolipoprotein-E-deficient (ApoE-/-) mice and human atherosclerotic carotid plaques. We found increased levels of CCL19 and CCL21 within the atherosclerotic lesions of the ApoE-/- mice, in human atherosclerotic carotid plaques, and in plasma of CAD patients. Whereas strong CCR7 expression was seen in T-cells from murine and human atherosclerotic plaques, circulating T-cells from angina patients showed decreased CCR7 expression. CCL19 and CCL21 promoted an inflammatory phenotype in T-cells and macrophages and increased matrix metalloproteinase (MMP) and tissue factor levels in the latter cell type. Although aggressive statin therapy increased CCR7 and decreased CCL19/CCL21 levels in peripheral blood from CAD patients, conventional therapy did not. CONCLUSIONS: The abnormal regulation of CCL19 and CCL21 and their common receptor in atherosclerosis could contribute to disease progression by recruiting T-cells and macrophages to the atherosclerotic lesions and by promoting inflammatory responses in these cells.

[Unexpected sudden death after percutaneous coronary intervention]. / Plutselig uventet dødsfall etter perkutan koronar intervensjon.

BACKGROUND: Myocarditis is one of several important differential diagnoses in patients presenting with chest pain or symptoms of heart failure. The prevalence of myocarditis is probably underestimated. In young patients with sudden cardiac death, myocarditis is a common finding at autopsy. MATERIAL AND METHODS: A previously healthy 54-year-old man presented with a first episode of chest pain. Smoking was the only risk factor for coronary artery disease. RESULTS: Plasma levels of both Troponin-I and CK-MB mass were negative at admission, but were elevated in a second sample. A subtotal stenosis in the left anterior descending artery was treated with PCI. The patient was discharged after four days. He was found dead at home six days after PCI. Autopsy revealed a massive myocarditis, no signs of myocardial necrosis and only minor coronary artery disease. INTERPRETATION: This case illustrates the importance of keeping less frequent differential diagnoses in mind when patients present with chest pain. Also, this case underscores the importance of keeping a high autopsy rate; for feedback to clinicians, for correct cause-of-death statistics and for research.

Plasma levels of soluble tumor necrosis factor receptor type I during the acute phase following complicated myocardial infarction predicts survival in high-risk patients.

OBJECTIVES: We sought to determine the relationship between circulating cytokine levels and clinical outcomes in patients with heart failure (HF) following acute myocardial infarction (AMI). BACKGROUND: Persistent inflammation plays a role in the development of HF, and various inflammatory cytokines predict cardiovascular events in acute coronary syndromes. METHODS: We measured plasma levels of interleukin (IL)-6, monocyte chemotractant protein 1, IL-10, and soluble tumor necrosis factor receptor type 1 (sTNFR1) during longitudinal testing over a period of two years in 234 patients with HF following AMI recruited for participation in the OPTIMAAL trial, focusing on the possible prognostic value of circulating cytokine levels in these patients. RESULTS: Measurement of sTNFR1 at baseline predicted all-cause mortality and cardiovascular death in patients with post-MI HF after adjustment for other biomarkers that have been shown to give prognostic information in HF patients, such as N-terminal B-type natriuretic peptide. CONCLUSIONS: Assessment of sTNFR1 levels might provide important prognostic information in patients who develop HF during the acute phase following AMI.

Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study.

BACKGROUND: Inflammation and matrix degradation may play a pathogenic role in chronic heart failure (CHF), and therefore, we examined whether thalidomide, a drug with potential immunomodulating and matrix-stabilizing properties, could improve left ventricular (LV) function in patients with CHF secondary to idiopathic dilated cardiomyopathy (IDCM) or coronary artery disease (CAD). METHODS AND RESULTS: Fifty-six patients with CHF and an LV ejection fraction (LVEF) <40% who were already on optimal conventional cardiovascular treatment were randomized to thalidomide (25 mg QD increasing to 200 mg QD) or placebo and followed up for 12 weeks. Our main findings were as follows: (1) During thalidomide treatment but not during placebo, there was a marked increase in LVEF (&7 EF units) along with a significant decrease in LV end-diastolic volume and heart rate. (2) This improvement in LVEF was accompanied by a decrease in matrix metalloproteinase-2 without any changes in its endogenous tissue inhibitor, suggesting a matrix-stabilizing net effect. (3) Thalidomide also induced a decrease in total neutrophil count and an increase in plasma levels of tumor necrosis factor-alpha, suggesting both proinflammatory and antiinflammatory effects. (4) The effect of thalidomide on LVEF was more marked in IDCM than in CAD, possibly partly reflecting that the former group was able to tolerate a higher thalidomide dosage. CONCLUSIONS: Although our results must be confirmed in larger studies that also examine the effects on morbidity and mortality, our findings suggest a role for thalidomide in the management of CHF in addition to traditional cardiovascular medications.

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.

Etanercept or intravenous immunoglobulin attenuates expression of genes involved in post-myocardial infarction remodeling.

OBJECTIVE: Persistently elevated levels of inflammatory cytokines such as tumor necrosis factor (TNF)alpha after acute myocardial infarction (MI) may contribute to maladaptive ventricular remodeling. The aim of the present study was to examine the effects of immunomodulatory therapy with recombinant soluble TNF receptor (TNFR:Fc) or intravenous immunoglobulin (IVIg) on left and right ventricular post-MI remodeling in rats. METHODS AND RESULTS: Adult male Sprague-Dawley rats were subjected to MI by left coronary artery ligation and randomized to treatment with vehicle, TNFR:Fc, or IVIg and sacrificed after 7 days. The main findings were that: (i) TNFR:Fc- and IVIg-treated rats developed less right ventricular (RV) hypertrophy compared to vehicle-treated controls. (ii) LV and arterial pressures in post-MI rats were not affected by the TNFR:Fc or IVIg treatment. (iii) As determined by real-time RT-PCR, both treatments reduced the expression of the hypertrophy-related genes, atrial natriuretic peptide and the ratio of beta/alpha-myosin heavy chains, and genes related to extracellular matrix remodeling (i.e., collagens I and III, matrix metalloproteinase [MMP]-2 and its tissue inhibitor TIMP-1) in the non-ischemic segment of LV and, in particular, in the RV. (iv) Treatment with IVIg, but not TNFR:Fc, reduced MMP-2 zymographic activity in the RV and the expression of genes for TNFalpha and monocyte chemoattractant protein-1. CONCLUSION: Therapy targeted directly against TNFalpha (i.e., TNFR:Fc) and a more general immunomodulatory approach (i.e., IVIg) in the acute phase of MI attenuates the cardiac remodeling process and expression of genes that are involved. These findings raise the possibility that initiation of immunomodulatory therapy post-MI could be beneficial in preventing the later development of heart failure.

Soluble CD40 ligand in acute and chronic heart failure.

AIMS: Inflammatory cytokines may play a pathogenic role in heart failure (HF). CD40-CD40 ligand (CD40L) interactions are important in atherogenesis and based on its role in inflammation we sought to evaluate the role of CD40L in human HF. METHODS AND RESULTS: Serum levels of soluble (s) CD40L were measured in 236 patients with acute HF following myocardial infarction, treated with either angiotensin-converting enzyme (ACE)-inhibition or angiotensin II blockade and followed for 2 years, and in 116 patients with chronic HF. Our main findings were: (i) patients with acute HF had increased sCD40L levels, particularly those with severe HF, diabetes, or hypertension; (ii) when these patients were followed longitudinally, persistently raised sCD40L levels were found throughout the observation period with no effect of captopril or losartan; (iii) the increase in sCD40L during follow-up was not seen in patients receiving warfarin therapy; (iv) patients with chronic HF also had raised sCD40L, significantly correlated with clinical severity, neurohormonal dysregulation, and left ventricular dysfunction; (v) studies from different blood compartments suggest that the vasculature of lower extremities and the failing myocardium itself may produce and secrete sCD40L in chronic HF. CONCLUSION: Our findings may suggest a pathogenic role for enhanced CD40-CD40L interactions in human HF.

Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction.

OBJECTIVES: We sought to determine the relationship between osteoprotegerin (OPG) and clinical outcomes in patients with heart failure (HF) after acute myocardial infarction (AMI). BACKGROUND: Arterial calcification is a prominent feature of arterial atherosclerosis and is associated with the occurrence of AMI. Osteoprotegerin is a recently discovered member of the tumor necrosis superfamily that may link the skeletal with the vascular system. METHODS: We assayed plasma OPG levels in 234 patients with AMI complicated with HF and their relation to adverse outcomes during follow-up in patients randomly assigned to angiotensin-converting enzyme inhibition or angiotensin II antagonism. Blood was sampled at baseline (median three days after AMI), one month, and at one and two years. RESULTS: Elevated plasma levels of OPG at baseline were associated with adverse outcomes during a median of 27 months follow-up; OPG remained an independent prognostic indicator also after adjustment for other known predictors of mortality and cardiovascular events after AMI (e.g., creatinine clearance, N-terminal B-type natriuretic peptide, high-sensitivity C-reactive protein). In non-survivors, plasma OPG levels were persistently elevated during longitudinal testing, suggesting that OPG may be of value for monitoring patients at risk. CONCLUSIONS: Osteoprotegerin is a novel marker for cardiovascular mortality and clinical events in patients with AMI complicated with HF. These findings are compatible with the hypothesis suggesting a possible association between mediators of bone homeostasis and cardiovascular disease.

Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S).

BACKGROUND: The effects of cholesterol-lowering treatment with statins on mortality and risk of cancer beyond the usual 5-6-year trial periods are unknown. We extended post-trial follow-up of participants in the Scandinavian Simvastatin Survival Study (4S) to investigate cause-specific mortality and incidence of cancer 5 years after closure of the trial. METHODS: 4S was a randomised double-blind trial of simvastatin or placebo in patients with coronary heart disease, serum total cholesterol 5.5-8.0 mmol/L, and serum triglycerides 2.5 mmol/L or lower. The double-blind period lasted for a median of 5.4 years (range for survivors 4.9-6.3) and ended in 1994. After the trial, most patients in both groups received open-label lipid-lowering treatment. National registers were used to assess mortality and causes of death and cancer incidence in the original treatment groups for a median total follow-up time of 10.4 years (range for survivors 9.9-11.3). Analysis was by intention to treat. FINDINGS: 414 patients originally allocated simvastatin and 468 assigned placebo died during the 10.4-year follow-up (relative risk 0.85 [95% CI 0.74-0.97], p=0.02), a difference largely attributable to lower coronary mortality in the simvastatin group (238 vs 300 deaths; 0.76 [0.64-0.90], p=0.0018). 85 cancer deaths arose in the simvastatin group versus 100 in the placebo group (0.81 [0.60-1.08], p=0.14), and 227 incident cancers were reported in the simvastin group versus 248 in the placebo group (0.88 [0.73-1.05], p=0.15). Incidence of any specific type of cancer did not rise in the simvastatin group. INTERPRETATION: Simvastatin treatment for 5 years in a placebo-controlled trial, followed by open-label statin therapy, was associated with survival benefit over 10 years of follow-up compared with open-label statin therapy for the past 5 years only. No difference was noted in mortality from and incidence of cancer between the original simvastatin group and placebo group.

Platelet activation in heart transplant recipients.

An inappropriate and persistent immune activation has been suggested to contribute to long-term mortality and morbidity after heart transplantation. Several lines of evidence suggest that platelets do not only promote thrombus formation, but also act as inflammatory cells. In the present study, we investigated if long-time survivors of heart transplantation (mean time since transplantation 6.5 yr) were characterized by enhanced platelet activation as assessed by different experimental approaches. Our main findings when comparing heart transplant recipients (n = 52) and age- and sex-matched healthy controls (n = 38) were: (i) platelets from heart transplant recipients showed enhanced expression of both P-selectin and CD63 as assessed by flow cytometry; (ii) platelets from these patients also contained significantly increased levels of soluble CD40 ligand and tended to release higher levels of this cytokine upon SFLLRN stimulation as assessed by enzyme immunoassay; (iii) heart transplant recipients had increased levels of soluble P-selectin in platelet-free plasma; and (iv) the enhanced platelet activation after heart transplantation was most pronounced in those with concomitant hypertension. These findings suggest that long-term survivors of heart transplantation are characterized by enhanced activation of platelets, possibly contributing to the persistent immune activation and clinical complications in these patients.