0000000000181704
AUTHOR
Stefan D. Anker
Association of statin use and clinical outcomes in heart failure patients : a systematic review and meta-analysis
Abstract Background The role of statins in patients with heart failure (HF) of different levels of left ventricular ejection fraction (LVEF) remains unclear especially in the light of the absence of prospective data from randomized controlled trials (RCTs) in non-ischemic HF, and taking into account potential statins’ prosarcopenic effects. We assessed the association of statin use with clinical outcomes in patients with HF. Methods We searched PubMed, EMBASE, Scopus, Google Scholar and Cochrane Central until August 2018 for RCTs and prospective cohorts comparing clinical outcomes with statin vs non-statin use in patients with HF at different LVEF levels. We followed the guidelines of the 2…
Whole blood endotoxin responsiveness in patients with chronic heart failure: the importance of serum lipoproteins.
Background Endotoxin [lipopolysaccharide (LPS)] may be an important stimulus for cytokine release in patients with chronic heart failure (CHF). We sought to investigate the relationship between whole blood endotoxin responsiveness and serum lipoprotein concentrations. It is not known if low-dose LPS is sufficient to stimulate immune activation. Methods and results Whole blood from 32 CHF patients (mean age 66±2 years, NYHA class 2.7±0.2, five female) and 11 healthy control subjects (mean age 47±4 years, six female) was stimulated with LPS at nine different concentrations (0.001 to 10 ng/mL), and tumor necrosis factor (TNF-α) release was quantified. Reference standard endotoxin at concentrat…
Is acute heart failure a distinctive disorder? An analysis from BIOSTAT-CHF
Aims: \ud This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients.\ud \ud Methods and Results: \ud The BIOSTAT‐CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between ac…
Inflammatory pathways in patients with heart failure and preserved ejection fraction.
Immune activation is well established in patients with chronic heart failure and reduced ejection fraction (HF and reduced EF) and is associated with an impaired prognosis. Patients with heart failure and preserved ejection fraction (HF and preserved EF) have an impaired prognosis as well. It is not known whether they have signs of immune activation.We studied patients with HF and preserved EF (n=17, NYHA II [n=7]/III [n=10]) and patients with HF and reduced EF (n=17 NYHA II [n=1]/III [n=16]) and 20 controls. Echocardiography demonstrated preserved ejection fraction (LVEF 59+/-9%), but LV hypertrophy in patients with preserved EF as compared with patients with reduced EF (LVEF 23+/-5%). We …
Inflammation in right ventricular dysfunction due to thromboembolic pulmonary hypertension
Activation of the immune system is well established in patients with chronic heart failure (CHF) and impaired left ventricular function. High levels of pro-inflammatory cytokines are associated with a poor prognosis. Chronic thromboembolic pulmonary hypertension (CTEPH) frequently leads to impaired right ventricular function. It is not known whether such patients display chronic immune activation as well.We studied 49 patients with CTEPH (50±2 years, right ventricular ejection fraction [RVEF] 29±2%, left ventricular ejection fraction [LVEF] 51±3%, mean±SEM) and compared their results with 17 patients with CHF (71±2 years, LVEF 23±1%) and 34 age-matched control subjects (age 57±2 years). We …
Exercise hyperventilation in chronic heart failure is not caused by systemic lactic acidosis
Background: Patients with heart failure have an abnormally high ventilatory response to exercise associated with gas exchange defects and reduced arterial pCO2. Aims: We examined the possibility of lactic acidosis as the stimulus to this increased ventilation that abnormally depresses pCO2 during exercise in heart failure. Method and results: We studied 18 patients with chronic heart failure. We measured VE/VCO2 slope during exercise, arterial blood gases and lactate concentrations during cardiopulmonary exercise testing (rest, peak exercise and one minute after the end of exercise). Neither VE/VCO2 slope nor arterial pCO2 were related to arterial lactate concentrations at peak exercise (r=…
Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.
Abstract Aims The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). Methods and results HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The …
Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure.
Bacterial endotoxin activity is elevated in patients with decompensated chronic heart failure (HF) and acts as a potent stimulus for immune activation. We sought to determine whether endotoxin, at an activity level seen in vivo (around 0.6 EU/ml), is sufficient to stimulate the secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha soluble receptor (sTNFR2) in ex vivo whole blood from patients with HF. We studied 15 patients with HF (aged 65 +/- 1.9 years, New York Heart Association class 2.1 +/- 0.3, left ventricular ejection fraction 31 +/- 5%; mean +/- SEM), of whom 5 had cardiac cachexia, and 7 healthy control subjects (59 +/- 5 years, p = NS). Reference endotoxin was added …
Serum uric acid and outcomes in patients with chronic heart failure through the whole spectrum of ejection fraction phenotypes: Analysis of the ESC-EORP Heart Failure Long-Term (HF LT) Registry
Background: Retrospective analyses of clinical trials indicate that elevated serum uric acid (sUA) predicts poor outcome in heart failure (HF). Uric acid can contribute to inflammation and microvascular dysfunction, which may differently affect different left ventricular ejection fraction (LVEF) phenotypes. However, role of sUA across LVEF phenotypes is unknown. Objectives: We investigated sUA association with outcome in a prospective cohort of HF patients stratified according to LVEF. Methods: Through the Heart Failure Long-Term Registry of the European Society of Cardiology (ESC-EORP-HFLT), 4,438 outpatients were identified and classified into: reduced (= 50% HFpEF) LVEF. Endpoints were t…
Differential contribution of dead space ventilation and low arterial pCO2 to exercise hyperpnea in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy
In chronic heart failure (CHF), the abnormally large ventilatory response to exercise (VE/VCO(2) slope) has 2 conceptual elements: the requirement of restraining arterial partial pressure of carbon dioxide (pCO(2)) from increasing (because of an increased ratio between increased physiologic dead space and tidal volume [VD/VT]) and the depression of arterial pCO(2) by further increased ventilation, which necessarily implies an important non-carbon dioxide stimulus to ventilation. We aimed to assess the contribution of these 2 factors in determining the elevated VE/VCO(2) slope in CHF. Thirty patients with CHF underwent cardiopulmonary exercise testing (age 65 +/- 11 years, left ventricular e…
Elevated levels of asymmetric dimethylarginine in chronic heart failure: a pathophysiologic link between oxygen radical load and impaired vasodilator capacity and the therapeuthic effect of allopurinol.
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide-dependent vasodilation. In 113 patients with chronic heart failure (CHF) and 26 controls, ADMA level was studied in relation to peripheral blood flow and vasodilator capacity. Further, the effects of allopurinol on concentrations of reactive oxygen species (ROS) and ADMA and peripheral vasodilator capacity were tested in a double-blind design. ADMA level was found to be elevated in CHF patients as compared with controls and increased in parallel with New York Heart Association (NYHA) class and exercise capacity (all P < 0.0001). The level of ADMA predicted resting blood flow (P < 0.05) and postischemic vasodilator…
Importance of selenium status in patients with chronic heart failure
Abstract Overactivity of the immune system may be a worthwhile therapeutic target for implementing prognostic improvements. Therefore the impact of lipopolysaccharide (LPS) desensitization on survival may help in the development of novel therapies. An understanding of the pathophysiology of the trace element selenium may complement such approaches, as recent data suggest that inflammatory responses are selenium-dependent.
Leukocyte Redistribution: Effects of Beta Blockers in Patients with Chronic Heart Failure
BACKGROUND:Overproduction of pro-inflammatory cytokines is a well established factor in the progression of chronic heart failure (CHF). Changes in cellular immunity have not been widely studied, and the impact of standard medication is uncertain. Here we investigate whether a leukocyte redistribution occurs in CHF and whether this effect is influenced by beta-blocker therapy. METHODOLOGY:We prospectively studied 75 patients with systolic CHF (age: 68+/-11 years, left ventricular ejection fraction 32+/-11%, New York Heart Association class 2.5+/-0.7) and 20 age-matched healthy control subjects (age: 63+/-10 years). We measured the response of cells to endotoxin exposure in vitro, analysed su…
Cachexia: a therapeutic approach beyond cytokine antagonism
Cachexia is seen in a number of chronic diseases, and it is always associated with a poor prognosis. Irrespective of etiology, the development of cachexia appears to share a common pathophysiological pathway. This includes induction of proteasome-dependent myofibril-degradation, which is thought to be secondary to stimulation by enhanced levels of pro-inflammatory cytokines. Elevation of tumor necrosis factor-alpha (TNFalpha) and other plasma cytokines has been demonstrated in many conditions associated with cachexia. Despite improved pathophysiological understanding, a specific treatment for cachexia has not yet been established. Whilst direct TNFalpha antagonism has therapeutic appeal, th…
Effect of noradrenaline and isoproterenol on lipopolysaccharide-induced tumor necrosis factor-alpha production in whole blood from patients with chronic heart failure and the role of beta-adrenergic receptors
Increased levels of tumor necrosis factor-alpha (TNF-alpha) correlate with poor prognoses in chronic heart failure (CHF). This study demonstrated that noradrenaline and isoproterenol inhibit TNF-alpha production in patients with CHF in ex vivo whole blood in a dose-dependent fashion. The beta-blocker bisoprolol abolishes this effect.
Heat shock protein 70 in patients with chronic heart failure: relation to disease severity and survival
Heat shock protein 70 (Hsp70) is essential for cellular recovery, survival and maintenance of cellular function. Research into the possible use of Hsp70 as a cytoprotective therapeutic agent is ongoing. Chronic heart failure (CHF) is a state associated with systemic inflammation, particularly in patients with cardiac cachexia. We hypothesised that circulating Hsp70 levels are elevated in patients with CHF, more so in cachechtic patients, and that Hsp70 levels would relate to mortality.We studied 107 patients (28 female, age 67+/-1 years, NYHA class 2.6+/-0.6 and LVEF 29+/-1%, mean+/-SEM) and 21 controls. Cardiac cachexia was present in 32 patients. Hsp70 was detectable in 41% of CHF patient…
The relationship between age and production of tumour necrosis factor-α in healthy volunteers and patients with chronic heart failure
Ageing is associated with an altered immune response. Elevated plasma levels of tumour necrosis factor-alpha (TNF-alpha) are present in patients with advanced chronic heart failure (CHF). However, the relationship between age and the immune response in CHF is unknown.We investigated the relationship between age and the TNF-alpha generating capacity of lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) in nine healthy control subjects (mean age 51.6+/-3.6 years, age range 39-75 years) and 22 stable patients with CHF (mean age 68.3+/-1.5 years, age range 52-78 years, NYHA class 3.0+/-0.2). We also tested the TNF-alpha generating capacity of all control subjects and …
The anti-CD14 antibody IC14 suppresses ex vivo endotoxin stimulated tumor necrosis factor-alpha in patients with chronic heart failure
Background: Activation of the endotoxin (LPS) receptor, CD14, leads to tumor necrosis factor-alpha (TNF) production. Plasma LPS activity is elevated in patients with severe chronic heart failure (CHF). An anti-CD14 antibody, IC14, blocks TNF production in healthy volunteers. It is not known whether IC14 prevents TNF production in CHF patients. Methods and results: Blood from 20 CHF patients (age 64±2.1 years, NYHA class 2.2±0.1, LVEF 27±3%, mean±SEM) was pre-incubated with 0.5, 1.0, 5.0, 10 and 50 μg/mL IC14 for 1 h followed by incubation with 1 or 10 ng/mL LPS for 6 h. Fourteen subjects served as controls (58±2.4 years). LPS-stimulated TNF release was 76% and 60% greater at 1 and 10 ng/mL …