Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: an international multicentre single-arm clinical trial.

AIMS: To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban. METHODS AND RESULTS: We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%). CONCLUSION: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.

Lipopolysaccharide responsiveness is an independent predictor of death in patients with chronic heart failure.

BACKGROUND: The origin of pro-inflammatory activation in chronic heart failure (HF) remains a matter of debate. Lipopolysaccharide (LPS) may enter the blood stream through the morphologically altered and leaky gut barrier. We hypothesized that lower LPS reactivity would be associated with worse survival as compared to normal or higher LPS reactivity. METHODS: LPS responsiveness was studied in 122 patients with chronic HF (mean±SD: age 67.3±10.3 years, 24 female, New York Heart Association class [NYHA] class: 2.5±0.8, left ventricular ejection fraction [LVEF]: 33.5±12.5%) and 27 control subjects of similar age (63.7±7.7 years, p>0.05). Reference LPS was added at increasing doses to ex vivo whole blood samples and necrosis factor-α (TNFα) was measured. Patients were subgrouped into good- and poor-responder status according to their potential to react to increasing doses of LPS (delta TNFα secretion). The optimal cut-off value was calculated by receiver-operator characteristic curve (ROC) analysis. RESULTS: A total of 56 patients with chronic HF died from any cause during follow-up. At 24 months, cumulative mortality was 16.4% (95% confidence interval 16.0-16.7%). The delta TNFα value representing the optimal cut-off for the prediction of mortality was 1522 pg/mL (24 months) with a sensitivity of 49.3% (95% confidence interval 37.2-61.4%) and specificity of 81.5% (95% confidence interval 61.9-93.6%). LPS responder status remained an independent predictor of death after multivariable adjustment (hazard ratio 0.09 for good- vs. poor-responders, 95% confidence interval 0.01-0.67, p<0.05). CONCLUSIONS: LPS responsiveness in patients with chronic HF is an independent predictor of death.

Inflammation in right ventricular dysfunction due to thromboembolic pulmonary hypertension.

OBJECTIVES AND BACKGROUND: 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. METHODS AND RESULTS: 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 studied serum levels of tumor necrosis factor-α (TNFα), its soluble receptors 1 and 2 (sTNFR1 and 2), interleukin-10 (IL-10) and plasma N-terminal-pro-B-type natriuretic peptide (NT-proBNP). Serum TNFα was not different in CTEPH compared with CHF patients (p=0.67) but both their levels were significantly higher than in controls (both p<0.001). Similar results were obtained for sTNFR1, sTNFR2, and IL-10. Levels of NT-proBNP were not different in patients with CTEPH or CHF (p=0.54), but significantly higher than in control subjects (both p<0.001). There were significant correlations between RVEF as assessed by magnetic resonance imaging and sTNFR1, sTNFR2, IL-6, high sensitivity C-reactive protein, and NT-proBNP (all p<0.05) in patients with CTEPH. CONCLUSION: Similar levels of immune activation as reflected by high levels of pro-inflammatory cytokines are present in patients with isolated right ventricular dysfunction due to CTEPH and patients with CHF and left ventricular dysfunction.

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 subsets of lymphocytes using flow cytometry, and assessed plasma levels of the pro-inflammatory markers interleukin 1, 6, tumor necrosis factor-alpha, and soluble tumor necrosis factor receptors 1 and 2. PRINCIPAL FINDINGS: While no differences in the number of leukocytes were noted between patients with CHF and healthy controls, we detected relative lymphopenia in patients with CHF (p<0.001 vs. control), mostly driven by reductions in T helper cells and B cells (both p<0.05). The number of neutrophils was increased (p<0.01). These effects were pronounced in patients who were beta-blocker naïve (32% of all patients with CHF). Increased plasma levels of soluble tumor necrosis receptor-1 correlated with the relative number of lymphocyte subsets. CONCLUSIONS: In patients with CHF, we detected a redistribution of leukocyte subsets, i.e. an increase in neutrophils with relative lymphopenia. These effects were pronounced in patients who were beta-blocker naïve. The underlying mechanism remains to be elucidated.

Elevated TNFalpha production in whole blood in patients with severe COPD: the potential link to disease severity.

OBJECTIVE: The relationship between tumour necrosis factor-alpha (TNFalpha), severity of pulmonary disease and nutritional depletion in chronic obstructive pulmonary disease (COPD) remains unclear. We aimed to clarify the role of lipopolysaccharide (LPS) as a potential stimulus of cytokine production and the role of these cytokines in the alteration of body composition in patients with different degrees of COPD. PATIENTS AND METHODS: We studied 29 weight-stable out-patients with different severites of COPD who had no evidence of recent infection or significant co-morbidity. Baseline serum TNFalpha levels and TNFalpha response to LPS in whole blood were measured in patients and 20 aged matched controls. RESULTS: Serum TNFalpha was significantly elevated in patients versus controls (2.1 +/- 0.3 vs. 1.1 +/- 0.1 pg/ml, mean +/- SEM, P = 0.007). In patients with COPD, we found a significant correlation between serum TNFalpha levels and disease severity, assessed as FEV(1) %predicted (r = 0.49, P = 0.02). Response to lipopolysaccharide did not differ significantly between patients and controls. However, within the patient group those with more severe disease (FEV(1) < or = 30% predicted, n = 12) had an enhanced response compared to patients with mild-to-moderate disease (all P < 0.05 for LPS > 1 ng/ml). Spontaneous TNFalpha production was 5.0 times higher in patients with severe COPD compared to mild-to-moderate COPD (P = 0.02). There was no relation between body composition and serum TNFalpha or TNFalpha response to LPS. CONCLUSION: Increasing airflow obstruction and hypercapnia are associated with an enhanced TNFalpha response in COPD.

Association between chronic dental infection and acute myocardial infarction.

INTRODUCTION: In patients with cardiovascular diseases several risk factors such as high blood pressure, diabetes, smoking and drinking habits, genetic disposition, and chronic inflammation must be considered. The aim of this study was to investigate whether there is a correlation between dental origin infections and the presence of an acute myocardial infarction (AMI). METHODS: A total of 125 patients who had experienced a myocardial infarction and 125 healthy individuals were included in this study. The oral examination was carried out following the consent of the ethics committee and the National Board for Radiation Protection and included the number of teeth, endodontically treated teeth, periodontal screening index (PSI), clinical attachment level, and radiographic apical lesions (radiograph examination). The medical examination included, among others, blood glucose level, C-reactive protein (CRP) serum levels, and leukocyte number. RESULTS: The study demonstrated that patients with AMI exhibited an unfavorable dental state of health. After statistical adjustment for age, gender, and smoking, they exhibited a significantly higher number of missing teeth (P = .001), less teeth with root canal fillings (P = .0015), a higher number of radiologic apical lesions (P = .001), and a higher PSI value (P = .001) compared with individuals without myocardial infarction. The medical data showed a nonsignificant correlation between CRP and the number of radiologic apical lesions. CONCLUSIONS: This study presents evidence that patients who have experienced myocardial infarction also exhibit an unfavorable dental state of health in comparison to healthy patients and suggests an association between chronic oral infections and myocardial infarction.

Impact of inflammatory markers on cardiovascular mortality in patients with metabolic syndrome.

BACKGROUND: Recent investigations suggest the inclusion of inflammatory markers in the definition of the metabolic syndrome (MS). The aim of this study was to address the role of C-reactive protein, fibrinogen, interleukin-6 (IL-6) and IL-18 (IL-18) on cardiovascular prognosis in accordance to MS. METHODS: A total of 1263 patients with documented coronary artery disease were prospectively included. We defined MS (MS yes: N=533, 42.2%) as the presence of at least three of the following criteria: triglycerides>or=150 mg/dl; low high-density lipoprotein cholesterol (men: <40 mg/dl women: <50 mg/dl); body mass index greater than 30 kg/m; blood pressure>or=130/85 mmHg; fasting glucose>or=100 mg/dl. In addition, we determined C-reactive protein, fibrinogen, IL-6 and IL-18 levels. RESULTS: Follow-up data (median 6.1 years) were available for 1257 patients (99.5%). 139 patients (11.1%) died from cardiovascular causes. Cardiovascular mortality was related to MS (MS yes: 15.1% versus MS no: 8.1%, P<0.0001) and was further increased by elevation of each inflammatory marker. To address whether elevation of inflammatory markers provides additional prognostic information, a subgroup analysis was performed including patients with MS. In a multivariate-adjusted model including all four inflammatory markers, only IL-18 could be identified as an independent predictor of cardiovascular mortality. CONCLUSION: The measurement of inflammatory markers, especially IL-18, adds important prognostic information with regard to the long-term prognosis of patients with MS.

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 microg/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 LPS, respectively, in CHF patients versus controls (p=0.07 and p=0.008). IC14 at concentrations of 5.0, 10 and 50 microg/mL substantially reduced TNF production in response to stimulation with LPS (all p<0.05). CD14 receptor density was similar in patients and controls. In controls, but not in CHF patients, there was a positive correlation between CD14 receptor density and TNF production (r=0.61, p=0.03). CONCLUSION: IC14 suppresses LPS-stimulated whole blood TNF production in patients with CHF and in normal subjects and therefore may represent a novel therapeutic strategy for CHF patients with systemic immune activation.

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-alpha) release was quantified. Reference standard endotoxin at concentrations of 0, 0.6, 1, and 3 EU/ml was added to whole blood from nine CHF patients (age 64+/-9.1 years, all NYHA class II, eight male) and incubated for 6 h, the TNF-alpha production being measured. Serum lipoproteins were quantified using standard techniques. In CHF patients, there was an inverse relationship between whole blood TNF-alpha release and serum cholesterol which was strongest at 0.6 ng/mL of LPS (r=-0.53, p=0.002). A similar although weaker relationship was found for serum HDL. No such correlation was found in healthy subjects or with serum LDL (all r(2)<0.1). Low concentrations of LPS induced a stepwise increase in TNF-alpha release from whole blood to concentrations well above those seen in CHF. CONCLUSIONS: Serum lipoproteins may play an important role in regulating LPS bioactivity in CHF. Very low LPS activity, at levels seen in vivo in CHF, can induce significant TNF-alpha production ex vivo.

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.

BACKGROUND: 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. METHODS AND RESULTS: 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 patients and in only 10% of controls. Overall serum levels were significantly higher in CHF patients vs. controls (7.13+/-1.34 vs. 0.38+/-0.26 ng/ml, p=0.004). Hsp70 levels were also higher in patients with advanced CHF according to NYHA class or the presence of cachexia (all p<0.05). There was no relation between Hsp70 and left ventricular ejection fraction, maximal oxygen consumption and several inflammatory cytokines (all p>0.05). During a median follow-up of 208 days (range 4-2745 days) 38 patients died. Cox proportional hazards analysis showed that increased Hsp70 did not predict survival (p=0.17). CONCLUSION: Hsp70 levels are elevated in CHF patients, particularly in those with cardiac cachexia and Hsp70 relates to disease severity but not to survival. The significance of the relationship of Hsp70 expression and morbidity in CHF needs further evaluation.

The relationship between age and production of tumour necrosis factor-alpha in healthy volunteers and patients with chronic heart failure.

BACKGROUND: 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. METHODS: 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 18 CHF patients in whole blood cultures. RESULTS: Subjects were subgrouped according to baseline TNF-alpha secretion in PBMC cultures into low- and high-responders, with the latter producing TNF-alpha even without LPS stimulation. High-responders produced more TNF-alpha than low-responders at all LPS doses (0.001-10 ng/ml, P<0.0001, repeated measures ANOVA), and high-responders were significantly older than low-responders (controls: 65.8+/-9.2 vs. 47.5+/-2.5 years; patients: 71.9+/-1.9 vs. 65.9+/-1.9 years, both P<0.05). Age correlated with TNF-alpha production in both patients and controls. This effect was independent of NYHA class. CONCLUSIONS: LPS-responsiveness appears to relate to age in both healthy controls and CHF patients. When assessing the immune status of CHF patients, age should therefore be considered an important confounding factor. In whole blood these findings could only be confirmed at the highest LPS concentration used, thus suggesting that certain factors in the blood may be able to abolish LPS activity at lower concentrations.

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 to venous blood at concentrations of 0.6, 1.0, and 3.0 EU/ml, and was incubated for 6 hours. Endotoxin induced a dose-dependent increase in TNF-alpha release (p <0.05 in all groups). Patients with noncachectic HF produced significantly more TNF-alpha compared with controls after stimulation with 0.6, 1.0, and 3.0 EU/ml of endotoxin (113 +/- 46 vs 22 +/- 4 [p = 0.009], 149 +/- 48 vs 34 +/- 4 [p = 0.002], and 328 +/- 88 vs 89 +/- 16 pg/ml [p = 0.002], respectively; mean +/- SEM). Patients with cardiac cachexia produced significantly less TNF-alpha compared with patients without cardiac cachexia for all given concentrations (all p <0.05, analysis of variance p = 0.02). Production of sTNFR2 was greater at all concentrations of endotoxin versus controls (all p <0.05, analysis of variance p = 0.002). Plasma endotoxin levels were higher in patients with cardiac cachexia (4.3 times higher than in control subjects, p <0.005). Thus, low endotoxin activity, at levels seen in vivo in patients with HF, induces significant TNF-alpha and sTNFR2 production ex vivo. These results suggest that elevated plasma endotoxin activity observed in patients with HF is of pathophysiologic relevance.