Alexander Ullmann

Interleukin 17 Drives Vascular Inflammation, Endothelial Dysfunction, and Arterial Hypertension in Psoriasis-Like Skin Disease

Objective— Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease. Approach and Results— Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17Aind/+ mice), associated with increased reactive oxygen species formation and circulating CD11b+ inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17Aind/+ mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase+CD11b+GR1+F4/80− cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-&agr; and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17Aind/+ mice. Conclusions— Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase+CD11b+GR1+F4/80− inflammatory cells. Depletion of the GR-1+ immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17Aind/+ mice.

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

BackgroundThe 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.MethodsIn 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.ResultsOverall, 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% (inte rquartile 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).ConclusionsQuality 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 registrationClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

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.

Relevance of depression for anticoagulation management in a routine medical care setting: results from the ThrombEVAL study program

Depressive symptoms have detrimental effects on quality of life and mortality. Poor adherence to a treatment regimen is a potential mechanism for the increased risk of adverse medical events associated with depression. Regarding oral anticoagulation with vitamin K antagonists, adherence is crucial for the outcome. Little is known about the clinical relevance of current depressiveness for anticoagulation treatment.

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 Virchows 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.

Rationale and design of three observational, prospective cohort studies including biobanking to evaluate and improve diagnostics, management strategies and risk stratification in venous thromboembolism: the VTEval Project

Introduction Venous thromboembolism (VTE) with its two manifestations deep vein thrombosis (DVT) and pulmonary embolism (PE) is a major public health problem. The VTEval Project aims to investigate numerous research questions on diagnosis, clinical management, treatment and prognosis of VTE, which have remained uncertain to date. Methods and analysis The VTEval Project consists of three observational, prospective cohort studies on VTE comprising cohorts of individuals with a clinical suspicion of acute PE (with or without DVT), with a clinical suspicion of acute DVT (without symptomatic PE) and with an incidental diagnosis of VTE (PE or DVT). The VTEval Project expects to enrol a total of approximately 2000 individuals with subsequent active and passive follow-up investigations over a time period of 5 years per participant. Time points for active follow-up investigations are at months 3, 6, 12, 24 and 36 after diagnosis (depending on the disease cohort); passive follow-up investigations via registry offices and the cancer registry are performed 48 and 60 months after diagnosis for all participants. Primary short-term outcome is defined by overall mortality (PE-related death and all other causes of death), primary long-term outcome by symptomatic VTE (PE-related death, recurrence of non-fatal PE or DVT). The VTEval Project includes three ‘all-comer’ studies and involves the standardised acquisition of high-quality data, covering the systematic assessment of VTE including symptoms, risk profile, psychosocial, environmental and lifestyle factors as well as clinical and subclinical disease, and it builds up a large state-of-the-art biorepository containing various materials from serial blood samplings. Ethics and dissemination The VTEval Project has been approved by the local data safety commissioner and the responsible ethics committee (reference no. 837.320.12 (8421-F)). Trial results will be published in peer-reviewed journals and presented at national and international scientific meetings. Trial registration number NCT02156401.

e-Health based management of patients receiving oral anticoagulation therapy: results from the observational thrombEVAL study

Essentials e‐Health based health care by an expert centre may advance management of oral anticoagulation. Outcome of patients was compared between an e‐health based coagulation service and regular care. Patients in the coagulation service cohort experienced a significantly better clinical outcome. Lower risk for adverse events was related to anticoagulation‐specific and non‐specific outcome.