Survival and quality of life after early discharge in low-risk pulmonary embolism.

INTRODUCTION: Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes. METHODS: The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism. RESULTS: The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of -9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001). CONCLUSIONS: Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.

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.

Sensitive troponin I assay in early diagnosis of acute myocardial infarction.

BACKGROUND: Cardiac troponin testing is central to the diagnosis of acute myocardial infarction. We evaluated a sensitive troponin I assay for the early diagnosis and risk stratification of myocardial infarction. METHODS: In a multicenter study, we determined levels of troponin I as assessed by a sensitive assay, troponin T, and traditional myocardial necrosis markers in 1818 consecutive patients with suspected acute myocardial infarction, on admission and 3 hours and 6 hours after admission. RESULTS: For samples obtained on admission, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve [AUC], 0.96), as compared with the troponin T assay (AUC, 0.85) and traditional myocardial necrosis markers. With the use of the sensitive troponin I assay (cutoff value, 0.04 ng per milliliter) on admission, the clinical sensitivity was 90.7%, and the specificity was 90.2%. The diagnostic accuracy was virtually identical in baseline and serial samples, regardless of the time of chest-pain onset. In patients presenting within 3 hours after chest-pain onset, a single sensitive troponin I assay had a negative predictive value of 84.1% and a positive predictive value of 86.7%; these findings predicted a 30% rise in the troponin I level within 6 hours. A troponin I level of more than 0.04 ng per milliliter was independently associated with an increased risk of an adverse outcome at 30 days (hazard ratio, 1.96; 95% confidence interval, 1.27 to 3.05; P=0.003). CONCLUSIONS: The use of a sensitive assay for troponin I improves early diagnosis of acute myocardial infarction and risk stratification, regardless of the time of chest-pain onset.

Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction.

CONTEXT: Introduction of highly sensitive troponin assays into clinical practice has substantially improved the evaluation of patients with chest pain. OBJECTIVE: To evaluate the diagnostic performance of a highly sensitive troponin I (hsTnI) assay compared with a contemporary troponin I (cTnI) assay and their serial changes in the diagnosis of acute myocardial infarction (AMI). DESIGN, SETTING, AND PATIENTS: A total of 1818 patients with suspected acute coronary syndrome were consecutively enrolled at the chest pain units of the University Heart Center Hamburg, the University Medical Center Mainz, and the Federal Armed Forces Hospital Koblenz, all in Germany, from 2007 to 2008. Twelve biomarkers including hsTnI (level of detection, 3.4 pg/mL) and cTnI (level of detection, 10 pg/mL) were measured on admission and after 3 and 6 hours. MAIN OUTCOME MEASURES: Diagnostic performance for AMI of baseline and serial changes in hsTnI and cTnI results at 3 hours after admission to the emergency department. RESULTS: Of the 1818 patients, 413 (22.7%) were diagnosed as having AMI. For discrimination of AMI, the area under the receiver operating characteristic (ROC) curve was 0.96 (95% CI, 0.95-0.97) for hsTnI on admission and 0.92 (95% CI, 0.90-0.94) for cTnI on admission. Both were superior to the other evaluated diagnostic biomarkers. The use of hsTnI at admission (with the diagnostic cutoff value at the 99th percentile of 30 pg/mL) had a sensitivity of 82.3% and a negative predictive value (for ruling out AMI) of 94.7%. The use of cTnI (with the diagnostic cutoff value at the 99th percentile of 32 pg/mL) at admission had a sensitivity of 79.4% and a negative predictive value of 94.0%. Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both hsTnI and cTnI assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value (for ruling in AMI) for hsTnI increased from 75.1% at admission to 95.8% after 3 hours, and for cTnI increased from 80.9% at admission to 96.1% after 3 hours. CONCLUSIONS: Among patients with suspected acute coronary syndrome, hsTnI or cTnI determination 3 hours after admission may facilitate early rule-out of AMI. A serial change in hsTnI or cTnI levels from admission (using the 99th percentile diagnostic cutoff value) to 3 hours after admission may facilitate an early diagnosis of AMI.

Thrombosis, fracture, and percutaneous removal of a patent foramen ovale closure device 1 month after successful deployment.

Several different devices have been developed for the percutaneous closure of interatrial defects and patent foramen ovale. Although the implantation of these devices is both safe and effective, a number of complications, both in the early and the late follow-up, may occur. We describe a case of device fracture manifested early (1 month after implantation) with the formation of massive thrombosis on the right atrial disc. The patient was treated with anticoagulants and the device was percutaneously retrieved. Our images allowed early noninvasive therapy and emphasize the need for echocardiographic follow-up early after implantation.

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.

Impact of metabolic syndrome on atherosclerotic burden and cardiovascular prognosis.

Patients with metabolic syndrome (MS) are at increased risk of cardiovascular atherosclerosis. The aim of this study was to evaluate the impact of MS on cardiovascular prognosis in context with atherosclerotic burden. A total of 811 patients with coronary heart disease (CHD) were included and carotid and leg arteries were examined using sonographic methods. Patients with low (CHD only, n = 428, 52.8%) or high atherosclerotic burden (CHD and peripheral atherosclerosis, n=383, 47.2%) were compared. Patients with >or=3 of the following criteria: triglycerides>or=150 mg/dl, high-density lipoprotein cholesterol<40 mg/dl (men) and <50 mg/dl (women), body mass index>30 kg/m2, blood pressure>or=130/85 mm Hg, and fasting glucose>or=100 mg/dl were defined as having MS (n=349, 43.0%). Follow-up data (median 6.7 years) were available for 807 patients (99.5%), and 175 patients (21.7%) experienced cardiovascular events (myocardial infarction, death, and stroke). The presence of MS significantly increased cardiovascular events in patients with low and high atherosclerotic burden (low: MS yes 21.2%, MS no 12.9%, p=0.02; high: MS yes 34.3%, MS no 26.5%, p=0.01). MS could be identified as an independent predictor for cardiovascular events in all patients (hazard ratio 1.7, 95% confidence interval 1.3 to 2.3, p<0.0001, adjusted) and patients with high atherosclerotic burden in particular (hazard ratio 1.8, 95% confidence interval 1.2 to 2.6, p=0.005, adjusted). In conclusion, MS markedly worsens the long-term prognosis of patients with both low and high atherosclerotic burden. Moreover, patients with high atherosclerotic burden and MS should be considered a high-risk population and treated accordingly.

Glutathione peroxidase-1 activity, atherosclerotic burden, and cardiovascular prognosis.

Recent findings suggest that erythrocyte intracellular glutathione peroxidase-1 (GPX-1) activity is related inversely to future cardiovascular events. The aim of this study is to evaluate the association of GPX-1 activity to extent of atherosclerosis, as well as its long-term prognosis in context with atherosclerotic burden. In a prospective study, we included 508 patients before coronary angiography. Atherosclerosis of carotid and leg arteries was documented using sonographic methods. Blood samples were drawn after an overnight fasting period, and GPX-1 activity was determined in washed erythrocytes. GPX-1 activity tended to decrease with increasing numbers of atherosclerotic vascular beds, so that patients without clinically relevant atherosclerosis had GPX-1 activity of 49.3 U/g hemoglobin compared with 46.0 U/g hemoglobin in patients with prevalent atherosclerosis in all 3 vascular beds (p = NS). Follow-up data (median 6.5 years) were available for 504 patients (99.2%), and 96 patients (19.0%) experienced cardiovascular events (cardiovascular death, infarction, and stroke). The event rate was inversely associated with level of GPX-1 activity divided into tertiles (hazard ratio 2.3, 95% confidence interval 1.4 to 4.0 for lowest vs highest tertile of GPX-1 activity, p = 0.002, adjusted). The highest event rate was found in persons with low GPX-1 activity and multivascular atherosclerosis (event rate 36.9%, p <0.0001). In conclusion, decreased red blood cell GPX-1 activity is associated with increased cardiovascular risk according to the extent of atherosclerosis.

Gender-specific diagnostic performance of a new high-sensitivity cardiac troponin I assay for detection of acute myocardial infarction.

BACKGROUND: The determination of cardiac troponin is essential for diagnosing myocardial infarction. A troponin I assay has recently been developed that provides the highest analytical sensitivity to date. METHODS: The analysis included 1560 patients with chest pain, of whom 1098 were diagnosed with non-coronary chest pain, 189 with unstable angina pectoris and 273 with non-ST-segment elevation myocardial infarction. The troponin I concentration was determined on admission (0 hours) and 3 hours later. The diagnostic algorithm incorporated troponin I elevation above the gender-specific 99th percentile as well as predefined relative or absolute 3-hour changes in the troponin I concentration (delta). RESULTS: The diagnostic criterion of troponin I above the 99th percentile resulted in a negative predictive value of 98.0% and 98.2% in men and women, respectively. For rule-in of non-ST-segment elevation myocardial infarction, the use of absolute deltas yielded higher positive predictive values and sensitivities compared to relative deltas. With detection rates of about 85% and 82% in men and women, respectively, non-ST-segment elevation myocardial infarction was diagnosed with a positive predictive value close to 84% in men and 80% in women. CONCLUSIONS: The investigational troponin I assay provides an excellent non-ST-segment elevation myocardial infarction rule out. With gender-specific differences, the application of absolute changes in troponin concentration was superior to relative changes to rule in patients with non-ST-segment elevation myocardial infarction.

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.

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.

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 pCO(2). AIMS: We examined the possibility of lactic acidosis as the stimulus to this increased ventilation that abnormally depresses pCO(2) during exercise in heart failure. METHOD AND RESULTS: We studied 18 patients with chronic heart failure. We measured VE/VCO(2) 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/VCO(2) slope nor arterial pCO(2) were related to arterial lactate concentrations at peak exercise (r = -0.16, p = 0.65 and r = -0.15, p = 0.6). During early recovery, patients with a high VE/VCO(2) slope had a particularly pronounced rise in arterial lactate and hydrogen ion concentrations (r = 0.57, p < 0.05 and r = 0.84, p < 0.0001) and yet their arterial pCO(2) rose rather than fell (r = 0.79, p < 0.001). The rise in arterial pCO(2) correlated with the increase in arterial hydrogen concentration (r = 0.78, p < 0.001) and with arterial pCO(2) at peak exercise (r = -0.76, p < 0.001). CONCLUSIONS: In heart failure VE/VCO(2) slope and low arterial pCO(2) at peak exercise are not related to the degree of systemic lactic acidosis. Lactic acidosis is therefore not a plausible mechanism of exercise induced hyperventilation.

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.

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 ejection fraction 34 +/- 15%, peak oxygen uptake 15.2 +/- 4 ml/kg/min, VE/VCO(2) slope 36.4). At rest and during exercise, arterial pCO(2) was measured and VD was calculated and separated into serial and alveolar components. VD/VT decreased from 0.57 at rest to 0.44 at peak exercise (p <0.01). VE/VCO(2) slope was correlated with peak exercise VD/VT (r = 0.67), the serial VD/VT ratio (r = 0.64), and alveolar VD/VT ratio (r = 0.51) at peak exercise (all p <0.01). VE/VCO(2) slope was also correlated with arterial pCO(2) (r = -0.75, p <0.001). Despite this, arterial pCO(2) was not related to peak oxygen uptake (r = 0.2) or to arterial lactate (r = -0.25) and only weakly to New York Heart Association functional class (F = 3.7). First, the increased VE/VCO(2) slope was caused by both the high VD/VT ratio and by other mechanisms, as shown by low arterial pCO(2) during exercise. Second, this latter component (depression of arterial pCO(2)) was not related to conventional measures of heart failure severity.

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.

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.

Clinical characteristics and survival of patients with chronic heart failure and prolonged QRS duration.

BACKGROUND: Abnormal prolongation of QRS duration is a common finding in patients with chronic heart failure, and is associated with an impaired prognosis. The optimum QRS duration for separating chronic heart failure patients with respect to prognosis has not been determined. Whilst resynchronisation of ventricular conduction may benefit patients with QRS>150 ms, this has yet to be determined for patients with moderate QRS prolongation. METHODS: We evaluated 155 patients with chronic heart failure (New York Heart Association class 2.6+/-0.8, mean+/-S.D.). The mean follow-up period was 838+/-748 days. Patients were sub-grouped according to QRS duration: <120 ms (normal QRS, n=82), 120-150 ms (moderate prolongation, n=44) and >150 ms (severe prolongation, n=29). RESULTS: The optimal QRS duration for stratifying patients for 2-year event free survival was 120 ms (receiver operating characteristic analysis: area under curve 0.73; 95% CI 0.64-0.81). Moderate prolongation of QRS duration was associated with a worse New York Heart Association class, peak oxygen consumption and left ventricular ejection fraction when compared to patients with normal QRS duration (all P<0.05). Patients with moderate prolongation of QRS duration had similar impairment of New York Heart Association class and peak oxygen consumption as compared with patients with QRS duration >150 ms (all P>0.05). CONCLUSIONS: The optimum QRS duration for stratifying patients for medium to long-term event-free survival was 120 ms. Heart failure patients with moderate QRS prolongation share similar impairment of exercise capacity and functional class to those with severe prolongation.

Prognostic information of glycogen phosphorylase isoenzyme BB in patients with suspected acute coronary syndrome.

Early and adequate risk stratification is essential in patients with suspected acute coronary syndrome (ACS). The aim of the present study was to investigate whether glycogen phosphorylase BB (GPBB) could add prognostic information in the context of contemporary sensitive troponin I determination and B-type natriuretic peptide (BNP). Patients with suspected ACS were consecutively enrolled at 3 German study centers from January 2007 through December 2008. Troponin I, GPBB, and BNP were determined at admission. Follow-up information on the combined end point of death, myocardial infarction, revascularization, and hospitalization owing to a cardiovascular cause was obtained 6 months after enrollment. In total 1,818 patients (66% men) were enrolled of whom 413 (23%) were diagnosed as having acute myocardial infarction and 240 (13%) as having unstable angina pectoris, whereas in 1,165 patients (64%) an ACS could be excluded. Follow-up information was available in 98% of patients; 203 events were registered. GPBB measured on admission predicted an unfavorable outcome with a hazard ratio of 1.24 (p <0.05) in an unadjusted Cox regression model and showed a tendency with a hazard ratio of 1.13 (p = 0.07) in a fully adjusted model. Kaplan-Meier analysis revealed a poorer outcome in patients with increased GPBB levels amendatory to the information provided by troponin I or BNP. In conclusion, GPBB measurement provides predictive information on midterm prognosis in patients with chest pain in addition to BNP and troponin I.