Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service--results from the prospective, multi-center, observational cohort study thrombEVAL.

BACKGROUND: The majority of studies on quality of oral anticoagulation (OAC) therapy with vitamin K-antagonists are performed with short-acting warfarin. Data on long-acting phenprocoumon, which is frequently used in Europe for OAC therapy and is considered to enable more stable therapy adjustment, are scarce. In this study, we aimed to assess quality of OAC therapy with phenprocoumon in regular medical care and to evaluate its potential for optimization in a telemedicine-based coagulation service. METHODS: In the prospective observational cohort study program thrombEVAL we investigated 2,011 patients from regular medical care in a multi-center cohort study and 760 patients from a telemedicine-based coagulation service in a single-center cohort study. Data were obtained from self-reported data, computer-assisted personal interviews, and laboratory measurements according to standard operating procedures with detailed quality control. Time in therapeutic range (TTR) was calculated by linear interpolation method to assess quality of OAC therapy. Study monitoring was carried out by an independent institution. RESULTS: Overall, 15,377 treatment years and 48,955 international normalized ratio (INR) measurements were analyzed. Quality of anticoagulation, as measured by median TTR, was 66.3% (interquartile range (IQR) 47.8/81.9) in regular medical care and 75.5% (IQR 64.2/84.4) in the coagulation service (P <0.001). Stable anticoagulation control within therapeutic range was achieved in 63.8% of patients in regular medical care with TTR at 72.1% (IQR 58.3/84.7) as compared to 96.4% of patients in the coagulation service with TTR at 76.2% [(IQR 65.6/84.7); P = 0.001)]. Prospective follow-up of coagulation service patients with pretreatment in regular medical care showed an improvement of the TTR from 66.2% (IQR 49.0/83.6) to 74.5% (IQR 62.9/84.2; P <0.0001) in the coagulation service. Treatment in the coagulation service contributed to an optimization of the profile of time outside therapeutic range, a 2.2-fold increase of stabile INR adjustment and a significant decrease in TTR variability by 36% (P <0.001). CONCLUSIONS: Quality of anticoagulation with phenprocoumon was comparably high in this real-world sample of regular medical care. Treatment in a telemedicine-based coagulation service substantially improved quality of OAC therapy with regard to TTR level, frequency of stable anticoagulation control, and TTR variability. TRIAL REGISTRATION: ClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

Impact of advanced age on the severity of normotensive pulmonary embolism.

The prevalence of pulmonary embolism (PE) increases progressively with age. Less data about the impact of increasing age on the severity of PE are available. The objectives of this study were to investigate the impact of increasing age on the severity of normotensive PE. Retrospective analysis of clinical, laboratory, radiological and echocardiagraphic data of normotensive patients with PE was performed. According to patients' age at the moment of acute PE event, the total number of 129 normotensive PE patients was subdivided into 4 age groups. In age groups 18-59, 60-69, 70-79 and 80-94 years were, respectively, a number of 30, 31, 33 and 35 patients included. Percentage of women in age groups increased with advanced age (P = 0.021). Systolic pulmonary artery pressure (PAP) (P < 0.0001) and frequency of incomplete or complete right bundle-branch block (RBBB) (P = 0.019), of right ventricular dysfunction (RVD) (P = 0.00031) and of submassive PE stadium with intermediate risk (P = 0.0016) increased significantly with growing age. Multivariable regression model confirmed an association between age and submassive PE [OR (per year) 1.04; 95 % CI, 1.02-1.07, P = 0.0020] as well as female gender and submassive PE (OR 2.45; 95 % CI, 1.10-5.50, P = 0.029) and tachycardia and submassive PE (OR 15.33; 95 % CI, 3.45-68.24, P = 0.00034). Advanced age, female gender and tachycardia are risk factors for a submassive PE with intermediate risk in normotensive PE patients. The percentage of PE patients with submassive PE, right ventricular overload, RVD, RBBB, elevated systolic PAP increases with advanced age.

Atherosclerosis and Its Impact on the Outcomes of Patients with Deep Venous Thrombosis.

Introduction: Atherosclerosis and pulmonary embolism (PE) affect cardiovascular mortality substantially. We aimed to investigate the impact of atherosclerosis on the outcomes of patients with deep venous thrombosis (DVT) and to identify the differences in DVT patients with and without PE. Methods: Patients with DVT with and without symptomatic atherosclerosis (defined as coronary artery disease, myocardial infarction and/or peripheral artery disease) as well as with and without PE under oral anticoagulation were enrolled during January 2011−April 2013 and compared. The impact of symptomatic atherosclerosis on several outcomes was analyzed. Results: Overall, 509 DVT patients (70.0 [56.0−77.0] years, 51.9% females) were included in this study. Among them, 179 (36.3%) had symptomatic atherosclerosis and 204 (40.1%) a concomitant PE. DVT patients with symptomatic atherosclerosis were older (74.0 [IQR 65.0−80.0] vs. 63.0 [48.0−75.0] years, p < 0.0001), more often male (56.4% vs. 43.9%, p = 0.0087) and had a higher prevalence of classical CVRF and a higher Charlson comorbidity index (7.00 [5.00−8.00] vs. 4.00 [2.00−6.00], p < 0.001). Symptomatic atherosclerosis was associated with increased mortality (HR 1.98 [95%CI 1.12−3.49], p = 0.018) and hospitalizations (HR 1.64 [95%CI 1.21−2.21], p = 0.0012) and primary long-term outcome (HR 1.99 [95%CI 1.31−3.04], p = 0.0013) during the 2 years follow-up-period in DVT patients. DVT patients without PE had diabetes mellitus (28.2% vs. 16.3%, p < 0.01) and symptomatic atherosclerosis (42.9% vs. 26.4%, p < 0.001) more often compared to DVT patients with PE, and symptomatic atherosclerosis was associated with isolated DVT (without PE) (OR 2.01 [95%CI 1.28−3.16], p < 0.01). Conclusions: Atherosclerosis was associated with isolated DVT (without PE) and increased mortality in DVT patients under oral anticoagulation. The profile of CVRF and comorbidities differed between DVT patients with and without a concomitant PE. In the case of DVT or PE, patients should be screened for concomitant atherosclerotic disease. Clinical Trial Registration: at clinicaltrials with Unique identifier NCT01809015.

Telemedicine-Based Specialized Care Improves the Outcome of Anticoagulated Individuals with Venous Thromboembolism-Results from the thrombEVAL Study.

Venous thromboembolism (VTE) is a life-threatening disease with risk of recurrence. Oral anticoagulation (OAC) with vitamin K antagonists (VKA) is effective to prevent thromboembolic recurrence. We aimed to investigate the quality of OAC of VTE patients in regular medical care (RMC) compared to a telemedicine-based coagulation service (CS). The thrombEVAL study (NCT01809015) is a prospective, multi-center study to investigate OAC treatment (recruitment: January 2011-March 2013). Patients were evaluated using clinical visits, computer-assisted personal interviews, self-reported data and laboratory measurements according to standard operating procedures. Overall, 360 patients with VTE from RMC and 254 from CS were included. Time in therapeutic range (TTR) was higher in CS compared to RMC (76.9% (interquartile range [IQR] 63.2-87.1%) vs. 69.5% (52.3-85.6%), p < 0.001). Crude rate of thromboembolic events (rate ratio [RR] 11.33 (95% confidence interval [CI] 1.85-465.26), p = 0.0015), clinically relevant bleeding (RR 6.80 (2.52-25.76), p < 0.001), hospitalizations (RR 2.54 (1.94-3.39), p < 0.001) and mortality under OAC (RR 5.89 (2.40-18.75), p < 0.001) were consistently higher in RMC compared with CS. Patients in RMC had higher risk for primary outcome (clinically relevant bleedings, thromboembolic events and mortality, hazard ratio [HR] 5.39 (95%CI 2.81-10.33), p < 0.0001), mortality (HR 5.54 (2.22-13.84), p = 0.00025), thromboembolic events (HR 6.41 (1.51-27.24), p = 0.012), clinically relevant bleeding (HR 5.31 (1.89-14.89), p = 0.0015) and hospitalization (HR 1.84 (1.34-2.55), p = 0.0002). Benefits of CS care were still observed after adjusting for comorbidities and TTR. In conclusion, anticoagulation quality and outcome of VTE patients undergoing VKA treatment was significantly better in CS than in RMC. Patients treated in CS had lower rates of adverse events, hospitalizations and lower mortality. CS was prognostically relevant, beyond providing advantages of improved international ratio (INR) monitoring.

Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates.

OBJECTIVE: Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance. METHODS AND RESULTS: Wistar rats were treated with PETN or GTN (10.5 or 6.6 microg/kg/min for 4 days). In contrast to GTN, PETN did not induce nitrate tolerance or cross-tolerance as assessed by isometric tension recordings in isolated aortic rings. Vascular protein and mRNA expression of HO-1 and ferritin were increased in response to PETN but not GTN. In contrast to GTN therapy, NO signaling, ROS formation, and the activity of ALDH-2 (as assessed by an high-performance liquid chromatography-based method) were not significantly influenced by PETN. Inhibition of HO-1 expression by apigenin induced "tolerance" to PETN whereas HO-1 gene induction by hemin prevented tolerance in GTN treated rats. CONCLUSIONS: HO-1 expression and activity appear to play a key role in the development of nitrate tolerance and might represent an intrinsic antioxidative mechanism of therapeutic interest.

Sustained atrial fibrillation increases the risk of anticoagulation-related bleeding in heart failure.

BACKGROUND: Oral anticoagulation therapy in individuals with atrial fibrillation (AF) reduces the risk of thromboembolic events at cost of an increased bleeding risk. Whether anticoagulation-related outcomes differ between patients with paroxysmal and sustained AF receiving anticoagulation is controversially discussed. METHODS: In the present analysis of the prospective multi-center cohort study thrombEVAL, the incidence of anticoagulation-related adverse events was analyzed according to the AF phenotype. Information on outcome was centrally recorded over 3 years, validated via medical records and adjudicated by an independent review panel. Study monitoring was provided by an independent institution. RESULTS: Overall, the sample comprised 1089 AF individuals, of whom n = 398 had paroxysmal AF and n = 691 experienced sustained AF. In Cox regression analysis with adjustment for potential confounders, sustained AF indicated an independently elevated risk of clinically relevant bleeding compared to paroxysmal AF [hazard ratio (HR) 1.40 (1.02; 1.93); P = 0.038]. For clinically relevant bleeding, a significant interaction of the pattern of AF type with concomitant heart failure (HF) was detected: HRHF 2.45 (1.51, 3.98) vs. HRno HF 0.85 (0.55, 1.34); Pinteraction = 0.003. In HF patients, sustained AF indicated also an elevated risk of major bleeding [HR 2.25 (1.26, 4.20); P = 0.006]. A simplified HAS-BLED score incorporating only information on age (> 65 years), bleeding history, and HF with sustained AF demonstrated better discriminative performance for clinically relevant bleeding than the original version: AUCHAS-BLED: 0.583 vs. AUCsimplifiedHAS-BLED: 0.642 (P = 0.004). CONCLUSIONS: In HF patients receiving oral anticoagulation, sustained AF indicates a substantially elevated risk of bleeding. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov , identifier: NCT01809015.

Management of Oral Anti-Coagulation in Patients with Heart Failure-Insights from the ThrombEVAL Study.

Patients with heart failure (HF) are frequently anti-coagulated with vitamin K-antagonists (VKAs). The use of long-acting VKA may be preferable for HF patients due to higher stability of plasma concentrations. However, evidence on phenprocoumon-based oral anti-coagulation (OAC) therapy in HF is scarce. The aim of this study was to assess the impact of the presence of HF on quality of phenprocoumon-based OAC and the subsequent clinical outcome. Quality of OAC therapy and the incidence of adverse events were analysed in a cohort of regular care (n = 2,011) from the multi-centre thrombEVAL study program (NCT01809015) stratified by the presence of HF. To assess the modifiability of outcome, results were compared with data from individuals receiving specialized care for anti-coagulation (n = 760). Overall, the sample comprised of 813 individuals with HF and 1,160 subjects without HF in the regular care cohort. Quality of OAC assessed by time in therapeutic range (TTR) was 66.1% (47.8%/82.8%) for patients with HF and 70.6% (52.1%/85.9%) for those without HF (p = 0.0046). Stratification for New York Heart Classification (NYHA)-class demonstrated a lower TTR with higher NYHA classes: TTRNYHA-I 69.6% (49.4%/85.6%), TTRNYHA-II 66.5% (50.1%/82.9%) and TTRNYHA-≥III 61.8% (43.1%/79.9%). This translated into a worse net clinical benefit outcome for HF (hazard ratio [HR] 1.63 [1.31/2.02]; p < 0.0001) and an increased risk of bleeding (HR 1.40 [1.04/1.89]; p = 0.028). Management in a specialized coagulation service resulted in an improvement of all, TTR (∆+12.5% points), anti-coagulation-specific and non-specific outcome of HF individuals. In conclusion, HF is an independent risk factor for low quality of OAC therapy translating into an increased risk for adverse events, which can be mitigated by specialized care.

NADPH oxidase accounts for enhanced superoxide production and impaired endothelium-dependent smooth muscle relaxation in BKbeta1-/- mice.

OBJECTIVE: Nitric oxide (NO)-induced vasorelaxation involves activation of large conductance Ca2+-activated K+ channels (BK). A regulatory BKbeta1 subunit confers Ca2+, voltage, and NO/cGMP sensitivity to the BK channel. We investigated whether endothelial function and NO/cGMP signaling is affected by a deletion of the beta1-subunit. METHODS AND RESULTS: Vascular superoxide in BKbeta1-/- was measured using the fluorescent dye hydroethidine and lucigenin-enhanced chemiluminescence. Vascular NO formation was analyzed using electron paramagnetic resonance (EPR), expression of NADPH oxidase subunits, the endothelial NO synthase (eNOS), the soluble guanylyl cyclase (sGC), as well as the activity and expression of the cyclic GMP-dependent kinase I (cGK-I) were assessed by Western blotting technique. eNOS, sGC, cGK-I expression and acetylcholine-induced NO production were unaltered in Bkbeta1-/- animals, whereas endothelial function was impaired and the activity of the cGK-I was reduced. Vascular O2- and expression of the NADPH oxidase subunits p67phox and Nox1 were increased. Endothelial dysfunction was normalized by the NADPH oxidase inhibitor apocynin. Potassium chloride- and iberiotoxin-induced depolarization mimicked the effect of BKbeta1-deletion by increasing vascular O2- in an NADPH-dependent fashion. CONCLUSIONS: The deletion of BKbeta1 causes endothelial dysfunction by increasing O2- formation via increasing activity and expression of the vascular NADPH oxidase.

Heart rate in pulmonary embolism.

Heart rate is a rapidly available risk stratification parameter in acute pulmonary embolism (PE). We aimed to investigate the effectiveness of heart rate in predicting the outcome in acute PE. Data of 182 patients with acute PE were analysed retrospectively. Logistic regression models were calculated to investigate the associations between heart rate and in-hospital death, myocardial necrosis, PE status and presence of right ventricular dysfunction (RVD), respectively. ROC curve and cut-off values for heart rate predicting RVD as well as intermediate risk PE status in normotensive PE patients and for heart rate predicting in-hospital death and myocardial necrosis in all PE patients were calculated. ROC analysis for heart rate predicting RVD and intermediate risk PE were 0.706 and 0.718, respectively, with cut-off value of 86 beats/min. Regression models showed associations between heart rate >85 beats/min and both RVD (OR 4.871, 95 % CI 2.256-10.515, P = 0.000055) and intermediate risk PE (OR 5.244, 95 % CI 2.418-11.377, P = 0.000027). In hemodynamically stable and unstable PE patients, logistic regression models showed a borderline significant association between tachycardia and in-hospital death (OR 7.066, 95 % CI 0.764-65.292, P = 0.0849) and a significant association between heart rate and myocardial necrosis (OR 0.975, 95 % CI 0.959-0.991, P = 0.00203). ROC analysis for heart rate predicting in-hospital death and myocardial necrosis revealed AUC of 0.655 and 0.703 with heart rate cut-off values of 99.5 beats/min and 92.5 beats/min, respectively. An elevated heart rate in acute PE is connected with a worse outcome. Effectiveness in the prediction of RVD, intermediate PE status, cardiac injury and in-hospital death is acceptable. The cut-off value for the prediction of RVD and intermediate risk PE status in normotensive PE is 86 beats/min, while tachycardia predicts in-hospital death.

Impact of cancer on the effectiveness of cardiac Troponin I to predict right ventricular dysfunction in acute pulmonary embolism.

BACKGROUND: Deep vein thrombosis (DVT) and pulmonary embolism (PE) are connected with a poor outcome in cancer patients. We aimed to investigate the impact of cancer on the effectiveness of cardiac Troponin I (cTnI) to predict right ventricular dysfunction (RVD) in acute PE. METHODS: We retrospectively analyzed the data of 182 patients with confirmed PE. PE patients were subdivided into two groups: (i) with concomitant active cancer disease or history of cancer, and (ii) without known cancer. Receiver operating characteristic (ROC) curves with area under the curve (AUC) was calculated for cTnI predicting RVD and related cut-off levels for both groups. RESULTS: Thirty-seven PE patients (20.3%) had an active cancer disease or a history of cancer. In contrast, 145 (79.7%) of the included PE patients did not have a known cancer disease or a history of cancer. In the PE group with cancer, analysis of the ROC curve showed an AUC of 0.76 for cTnI predicting RVD with an optimal cut-off value of 0.04 ng/mL; the risk of misclassification was 25.0%. In the PE group without cancer, AUC was 0.81 for cTnI predicting RVD with an optimal cut-off value of 0.015 ng/mL; the risk of misclassification was 24.9%. CONCLUSIONS: cTnI is effective for predicting RVD in PE patients with and without cancer. However, the effectiveness of cTnI to predict RVD was higher in PE patients without cancer than in those with cancer or a history of cancer.

D-dimer for risk stratification in haemodynamically stable patients with acute pulmonary embolism.

PURPOSE: Patients with submassive pulmonary embolism (PE) have a higher short-term mortality than those with low-risk PE. Rapid identification of submassive PE is important for adequate treatment of non-massive PE. We aimed to investigate the utility of D-dimer for the prediction of submassive PE stadium in normotensive PE patients. PATIENTS AND METHODS: Normotensive PE patients were classified into submassive or low-risk PE groups. In addition to the comparison of the groups, area under the curve (AUC) and D-dimer cut-off for the prediction of submassive PE stadium, multi-variate logistic regression for association between D-dimer values above this cut-off and submassive PE stadium were also calculated. RESULTS: The data of 129 normotensive PE patients (59.7% women, mean age 70.0 years (60.7/81.0)) were analysed retrospectively. Patients with submassive PE were older (75.0 years (61.7/81.0) vs. 66.5 years (55.7/74.2), P=0.026) and more frequently female (63.6% vs. 53.8%, P=0.35). Heart rate (100.0beats/min (85.0/108.0) vs. 80.0beats/min (70.0/96.2), P<0.0001), systolic pulmonary-artery pressure (41.55±16.79mmHg vs. 22.62±14.81mmHg, P<0.0001), and D-dimer (2.00mg/l (1.09/3.98) vs. 1.21mg/l (0.75/1.99), P=0.011) were higher in patients with submassive PE. D-dimer values >1.32mg/l were indicative of submassive PE and shock-index ≥0.7. The effectiveness (AUC) of the test was 0.63 for submassive PE and 0.64 for shock-index ≥0.7. D-dimer values >1.32mg/l were associated with submassive PE stadium (OR 3.81 (95% CI: 1.74-8.35), P=0.00083) as well as with systolic blood pressure (OR 0.98 (95% CI: 0.97-0.99), P=0.033), heart rate (OR 1.02 (95% CI: 1.00-1.04), P=0.023) and shock-index value (OR 15.89 (95% CI: 1.94-130.08), P=0.0099). CONCLUSIONS: D-dimer values >1.32mg/l are indicative of submassive PE stadium and shock-index ≥0.7. Efficacy of D-dimer for predicting submassive PE stadium was only weak to moderate.

The risk factor age in normotensive patients with pulmonary embolism: Effectiveness of age in predicting submassive pulmonary embolism, cardiac injury, right ventricular dysfunction and elevated systolic pulmonary artery pressure in normotensive pulmonary embolism patients.

INTRODUCTION: Right ventricular dysfunction (RVD), submassive pulmonary embolism (PE), elevated systolic pulmonary artery pressure (sPAP), elevated cardiac troponin I (cTnI) and old age are well-known risk factors for poor outcome in acute normotensive PE. The aim of this analysis was to calculate age cut-off values to predict submassive PE, cardiac injury, RVD and elevated sPAP in normotensive PE patients. METHODS: Retrospective analysis of clinical, laboratory, radiological and echocardiographic data of normotensive PE patients (2006-2011) was performed. Receiver operating characteristic (ROC) curves and Youden indexes were used to test the effectiveness of using patients' ages at the PE event to predict a submassive PE, cardiac injury (elevated cTnI >0.1ng/ml), RVD and elevated sPAP (>30mmHg) in normotensive PE patients and to calculate optimal cut-off values. Patients >76years were compared to those aged ≤76years. RESULTS: 129 normotensive PE patients (59.7% women) met the inclusion criteria and were included in this analysis. The optimal cut-off value for patient ages to predict submassive PE, cardiac injury (elevated cTnI >0.1ng/ml), RVD and elevated sPAP (>30mmHg) was 76.5, 81.5, 66.5 and 66.5years, respectively, with moderate effectiveness (AUC 0.69, 0.58, 0.71 and 0.69, respectively). Patients >76years old had higher percentages of submassive PE (91.1% vs. 63.1%, P=0.000680), RVD (91.1% vs. 58.3%, P=0.000119), sPAP (42.64±16.70 vs. 29.24±17.56mmHg, P=0.000044) and cTnI (0.22±0.40 vs. 0.10±0.25ng/ml, P=0.00488). CONCLUSIONS: Age is an important prognostic factor in acute normotensive PE. In addition to cTn and RVD, age should be taken into account in determining the risk stratification for acute PE.

Evaluation of oral anticoagulation therapy: rationale and design of the thrombEVAL study programme.

BACKGROUND: Since decades, oral anticoagulation (OAC) with vitamin K antagonists (VKA) is an established therapy for both prevention and treatment of thromboembolism in daily clinical routine. Increasing life expectancy, demographic changes, and novel oral anticoagulants have led to an increasing complexity of medical therapy. However, data on quality and management of VKA therapy with phenprocoumon in current medical care are limited. Our aim is to investigate the quality of OAC with VKA in current health care and to evaluate the potential for improvements. STUDY DESIGN: The investigator-initiated thrombEVAL study programme comprises two cohorts of patients treated with vitamin K antagonists for oral anticoagulation therapy in real-life settings: a multicentre cohort of patients in regular medical care and a multilocal, single-centre cohort of patients in a telemedicine-based coagulation service. The study programme is expected to enrol a total number of approximately 2000 to 2500 patients. Both cohorts will build on a detailed clinical assessment of participants and anticoagulation therapy at study enrolment. Subsequently active and passive follow-up investigations are carried out to document and validate complications of the treatment. The primary short-term outcome is the distribution of time in therapeutic range; the primary long-term outcome comprises the composite of stroke, systemic embolism, myocardial infarction, major and clinically relevant bleeding, and death. CONCLUSIONS: The thrombEVAL project will provide a large prospective observational cohort of patients predominantly treated with phenprocoumon. It will evaluate the quality of oral anticoagulation in regular medical care and a telemedicine-based coagulation service.

History of deep vein thrombosis is a discriminator for concomitant atrial fibrillation in pulmonary embolism.

BACKGROUND: Pulmonary embolism (PE) is the consequence of deep vein thrombosis (DVT) in 70% of all cases. Although, PE and DVT are commonly related to risk factors of Virchow's triad, both entities are linked to cardiovascular risk factors, but risk factors seem differently important in both entities. OBJECTIVES: We aimed to investigate clinical profile and outcome of patients with PE history stratified by concomitant DVT. PATIENTS/METHODS: Data from the observational multi-center thrombEVAL-study were analyzed. RESULTS: The sample (N=2,318) comprised 295 PE patients, of whom 69.2% (N=204) had DVT. Individuals without DVT were older and had higher prevalence of concomitant atrial fibrillation (AF), chronic lung diseases, coronary artery disease, heart failure and hypertension. Multivariable regression revealed an independent association of AF (Odds Ratio (OR) 3.17, 95% CI 1.63-6.18, P<0.001) and coronary artery disease (OR 2.31, 95% CI 1.15-4.66, P=0.019) with PE without DVT. There was higher frequency of permanent AF in individuals without DVT, whereas paroxysmal AF was more prevalent in individuals with DVT. All AF subtypes were independently associated with PE without DVT with increasing ORs from paroxysmal to permanent AF. PE patients with and without DVT did not differ in survival (P=0.32) and cost-relevant clinical outcome (P=0.26) during follow-up. AF in PE patients was associated with cost-relevant clinical outcome (Hazard Ratio (HR) 1.78, 95% CI 1.03-3.09, P=0.040), but no significant difference in survival (HR 0.93, 95% CI 0.35-2.50, P=0.88) was observed. CONCLUSIONS: History of DVT is a significant discriminator for clinical profile of PE patients. Individuals without DVT had more often cardiac and pulmonary disease with strongest association with AF. Data advocate a potential link between AF and PE. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov, Unique identifier NCT01809015.

Symptoms of depression and anxiety predict mortality in patients undergoing oral anticoagulation: Results from the thrombEVAL study program.

BACKGROUND/OBJECTIVES: Depression and anxiety are highly prevalent in cardiovascular patients. Therefore, we examined whether the 4-item Patient Health Questionnaire (PHQ-4, measuring symptoms of depression and anxiety) predicts all-cause mortality in outpatients with long-term oral anticoagulation (OAC). METHODS: The sample comprised n=1384 outpatients from a regular medical care setting receiving long-term OAC with vitamin K antagonists. At baseline, symptoms of anxiety and depression were assessed with the PHQ-4 and the past medical history was taken. The outcome was all-cause mortality in the 24 month observation period. The median follow-up time was 13.3 months. RESULTS: N=191 patients from n=1384 died (death rate 13.8%). Each point increase in the PHQ-4 score was associated with a 10% increase in mortality (hazard ratio [HR] 1.10, 95% confidence interval [95% CI] 1.05-1.16) after adjustment for age, sex, high school graduation, partnership, smoking, obesity, frailty according to the Barthel Index, Charlson Comorbidity Index and CHA2DS2-VASc score. The depression component (PHQ-2) increased mortality by 22% and anxiety (GAD-2) by 11% respectively. Neither medical history of any mental disorder, nor intake of antidepressants, anxiolytics or hypnotics predicted excess mortality. CONCLUSIONS: Elevated symptoms of depression and, to a lesser degree, symptoms of anxiety are independently associated with all-cause mortality in OAC outpatients. The PHQ-4 questionnaire provides valuable prognostic information. These findings emphasize the need for implementing regular screening procedures and the development and evaluation of appropriate psychosocial treatment approaches for OAC patients.

A 56-year-old man with co-prevalence of Leriche syndrome and dilated cardiomyopathy: case report and review.

We report about a 56-year-old man with dyspnoea and leg pain diagnosed with Leriche syndrome and chronic heart failure caused by dilated cardiomyopathy (DCM) with acute cardiac decompensation. Optimising of chronic heart failure therapy with diuretic and antihypertensive drugs leaded to recompensation. A defibrillator was implanted, and afterwards surgical therapy of Leriche syndrome was planned.Leriche syndrome is an uncommon variant of atherosclerotic occlusive disease characterised by total occlusion in abdominal aorta and/or both iliac arteries. If aortic stenosis develops slowly, collateral vascular circulation can be found frequently. Typical symptoms are claudication, symptoms related to an arterial insufficiency of the lower extremities, erectile dysfunction and weight loss. Risk factors of Leriche syndrome are diabetes mellitus, hypertension, hyperlipaemia and smoking. Further it is often associated with chronic renal failure and coronary artery disease. Diagnosis is normally made by computed tomography (CT) or magnetic resonance imaging (MRI). Standard therapy is surgical revascularisation.DCM is a common cause of a congestive heart failure, which could be induced by coronary artery disease, hypertension, toxic, metabolic, inflammatory and infectious agents, and inherited gene defects.

Right ventricular dysfunction in hemodynamically stable patients with acute pulmonary embolism.

BACKGROUND: Echocardiography for risk stratification in hemodynamically stable patients with pulmonary embolism (PE) is well-established. Right ventricular dysfunction (RVD) is associated with an elevated mortality and adverse outcome. The aim of our study was to compare RVD criteria and investigate the role of elevated systolic pulmonary artery pressure (sPAP) in the diagnosis of RVD. METHODS: We retrospectively analyzed the echocardiographic and laboratory data of all hemodynamically stable patients with confirmed PE (2006-2011). The data were compared with three different definitions of RVD: Definition 1: RV dilatation, abnormal motion of interventricular septum, RV hypokinesis or tricuspid regurgitation. Definition 2: as with definition 1 but including elevated sPAP (>30mmHg). Definition 3: elevated sPAP (>30mmHg) as single RVD criterion. RESULTS: A total number of 129 patients (59.7% women, age 70.0years (60.7/81.0)) were included in this study. Median Troponin I level was measured as 0.02ng/ml (0/0.14); mean sPAP 33.9±18.5mmHg. The troponin cut-off levels for predicting a RVD of the 3 RVD definitions were in definition 1-3: >0.01ng/ml, >0.01ng/ml and >0.00ng/ml. Analysis of the ROC curve showed an AUC for RVD definitions 1-3: 0.790, 0.796 and 0.635. CONCLUSIONS: The combination of commonly used RVD criteria with added elevated sPAP improves the diagnosis of RVD in acute PE. Troponin I values of >0.01ng/ml in acute PE point to an RVD.

Hyperglycemia and oxidative stress in cultured endothelial cells--a comparison of primary endothelial cells with an immortalized endothelial cell line.

Diabetes mellitus is a major risk factor for the development of cardiovascular disease and oxidative stress plays an important role in this process. Therefore, we investigated the effects of hyperglycemia on the formation of reactive oxygen species (ROS) and nitric oxide/cGMP signaling in two different endothelial cell cultures. Human umbilical vein endothelial cells (HUVEC) and EA.hy 926 cells showed increased oxidative stress and impaired NO-cGMP signaling in response to hyperglycemia. The major difference between the two different cell types was the dramatic decrease in viability in HUVEC whereas EA.hy cells showed rather increased growth under hyperglycemic conditions. Starvation led to an additional substantial decrease in viability and increased superoxide formation in HUVEC. Both endothelial cell types, HUVEC and EA.hy 926, may be used as models for vascular hyperglycemia. However, high growth medium should be used to avoid starvation-induced oxidative stress and cell death.

Hydralazine is a powerful inhibitor of peroxynitrite formation as a possible explanation for its beneficial effects on prognosis in patients with congestive heart failure.

The hemodynamic and anti-ischemic effects of nitroglycerin (GTN) are rapidly blunted as a result of the development of nitrate tolerance. Hydralazine has been shown to prevent tolerance in experimental and clinical studies, all of which may be at least in part secondary to antioxidant properties of this compound. The antioxidant effects of hydralazine were tested in cell free systems, cultured smooth muscle cells, isolated mitochondria, and isolated vessels. Inhibitory effects on the formation of superoxide and/or peroxynitrite formation were tested using lucigenin and L-012 enhanced chemiluminescence as well as DHE-fluorescence. The peroxynitrite scavenging properties were also assessed by inhibition of nitration of phenol. Prevention of impairment of NO downstream signaling and GTN bioactivation was determined by measurement of P-VASP (surrogate parameter for the activity of the cGMP-dependent kinase-I, cGK-I) and mitochondrial aldehyde dehydrogenase (ALDH-2) activity. Hydralazine dose-dependently decreased the chemiluminescence signal induced by peroxynitrite from SIN-1 and by superoxide from HX/XO in a cell free system, by superoxide in smooth muscle cells and mitochondria acutely challenged with GTN. Moreover, hydralazine inhibited the peroxynitrite-mediated nitration of phenols as well as proteins in smooth muscle cells in a dose-dependent fashion. Finally, hydralazine normalized impaired cGK-I activity as well as impaired vascular ALDH-2 activity. Our results indicate that hydralazine is a highly potent radical scavenger. Thus, the combination with isosorbide dinitrate (ISDN) will favorably influence the nitroso-redox balance in the cardiovascular system in patients with congestive heart failure and may explain at least in part the improvement of prognosis in patients with chronic congestive heart failure.

Heterozygous deficiency of manganese superoxide dismutase in mice (Mn-SOD+/-): a novel approach to assess the role of oxidative stress for the development of nitrate tolerance.

Nitroglycerin (GTN)-induced tolerance was reported to be associated with increased levels of reactive oxygen species (ROS) in mitochondria. In the present study, we further investigated the role of ROS for the development of nitrate tolerance by using heterozygous manganese superoxide dismutase knock-out mice (Mn-SOD+/-). Mn-SOD is acknowledged as a major sink for mitochondrial superoxide. Vasodilator potency of mouse aorta in response to acetylcholine and GTN was assessed by isometric tension studies. Mitochondrial ROS formation was detected by 8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt (L-012)-enhanced chemiluminescence and mitochondrial aldehyde dehydrogenase (ALDH-2) activity was determined by a high-performance liquid chromatography-based assay. Aortic rings from Mn-SOD+/- mice showed normal endothelial function and vasodilator responses to GTN. In contrast, preincubation of aorta with GTN or long-term GTN infusion caused a marked higher degree of tolerance as well as endothelial dysfunction in Mn-SOD+/- compared with wild type. Basal as well as GTN-stimulated ROS formation was significantly increased in isolated heart mitochondria from Mn-SOD+/- mice, correlating well with a marked decrease in ALDH-2 activity in response to in vitro and in vivo GTN treatment. The data presented indicate that deficiency in Mn-SOD leads to a higher degree of tolerance and endothelial dysfunction associated with increased mitochondrial ROS production in response to in vitro and in vivo GTN challenges. These data further point to a crucial role of ALDH-2 in mediating GTN bioactivation as well as development of GTN tolerance and underline the important contribution of ROS to these processes.