Differences in treatment strategies for LDL-cholesterol reduction in a university lipid clinic vs. standard care apart from the use of PCSK9 inhibitors.

BACKGROUND: Lipid-lowering therapy (LLT) in patients with cardiovascular disease (CVD) is insufficient despite clear guideline recommendations. Lipid clinics have specialized in patients with dyslipidemia, but the magnitude and reduction of low-density lipoprotein cholesterol (LDL-C) in lipid clinics has not yet been studied in depth. OBJECTIVE: To assess LDL-C reduction in very high-risk CVD patients achieved in a lipid clinic through different forms of LLT in comparison to standard care without the initiation of PSCK9 inhibitors. METHODS: Data from 96 lipid clinic patients were analyzed retrospectively and compared to 84 standard care patients. Very high-risk patients were defined according to the European Society of Cardiology (ESC). Different combinations of LLT focusing on statins and ezetimibe were investigated. Achievement of LDL-C treatment goals according to ESC guidelines as well as LDL-C reduction were assessed. RESULTS: Baseline and follow-up data of 180 very high-risk CVD patients (mean age 67.7 (±9.8) y; 60.6% male) were used. Achievement of the LDL-C goal in lipid clinic patients increased significantly from 14.6% at baseline to 41.7% at the latest visit (p<0.001) while standard care patients improved from 21.4% to 33.3% (p=0.08). The largest relative LDL-C reduction via an adjustment in LLT was achieved by initiation of high-intensity statins (50.8 ± 4.9%, n = 5, p < 0.05). CONCLUSION: Treatment in a lipid clinic leads to a superior LDL-C goal achievement in very high-risk CVD patients as compared to standard care with the highest reduction under LLT with high-intensity statins and ezetimibe. Referral algorithms have to be established for high-risk patients.

Mechanical atherothrombectomy improves endothelial function through plaque burden reduction in PAD.

Background: Endothelial dysfunction defines outcomes and serves as a surrogate parameter for the progression of cardiovascular disease. For symptomatic peripheral artery disease (PAD) endovascular treatment is the primary revascularization strategy, which affects endothelial function. Interventional mechanical atherothrombectomy (MATH) provides advantages when treating complex atherosclerotic and thrombotic lesions. We now aimed to determine the impact and mechanisms of MATH on endothelial function. Patients and methods: Endothelial function was determined using flow-mediated dilation (FMD) before and after lower limb intervention with a six-month follow-up in the target and control vessel in 15 PAD MATH+DCB treated patients and compared to 15 non-Math controls. In a further cohort of 20 patients the impact of MATH and DCB on vascular structure and virtual histology was assessed through intravascular ultrasound (IVUS) and compared to DCB treatment alone. Results: Improved endothelial function after 6 months was observed in both groups for the target and nontarget vessel. When comparing the changes from baseline endothelial function, treatment with MATH+DCB was superior to DCB treatment in the target vessel. IVUS revealed a greater improvement in luminal area and plaque burden reduction after MATH treatment. Virtual histology disclosed MATH-associated changes in plaque composition evidenced by alterations in fibrous volume and reductions in superficial calcium. Conclusions: We demonstrate an improved endothelial function after MATH treatment as compared to DCB treatment. The improved vessel function is evidenced by MATH-related plaque burden reduction, improved luminal gain and a decrease in superficial calcification. Clinicaltrials.gov: NCT04092972.

Peripheral artery disease in Germany (2009-2018): Prevalence, frequency of specialized ambulatory care and use of guideline-recommended therapy - A population-based study.

BACKGROUND: Peripheral artery disease (PAD) patients have high morbidity and mortality rates, demonstrating a need for improved treatment strategies. While underuse and undertreatment have been reported, there is no clear picture of patterns in population-level disease prevalence, prescription of guideline-recommended pharmacotherapy, or frequency of contact with dedicated specialists. We present population-level data on changes in prevalence, care and treatment of PAD from 2009 to 2018 in Germany. METHODS: We analyzed the ambulatory claims data for all statutorily insured patients comprising 70.1 million patients each year and 87% of the German population. Prevalence was assessed by documentation of PAD and stratified by age and sex within the 10-year study timeframe. In addition, current ambulatory care, stratified by vascular specialists (vascular surgeons or angiologists), internists, cardiologists and primary care physicians, were examined. FINDINGS: Prevalence increased from 1·85% in 2009 to 3·14% in 2018, affecting 2·3 million patients in 2018 and more males (55%) than females (45%). A low level of visits to vascular specialists, with 11·1% receiving care from vascular surgeons and 8·1% from angiologists, was shown. Moreover, analysis of guideline-recommended prescriptions revealed increasing, but still insufficient, prescription frequencies among PAD patients between 2009 and 2016, from 42·6% to 56% for statins and from 40·2% to 48·0% for antiplatelets. INTERPRETATION: Our results show that the prevalence of PAD in Germany, as assessed by outpatient PAD documentation, is increasing and PAD patients are underutilizing specialized vascular care; moreover, the prescription frequency of guideline-recommended therapies remains low. There is a clear need to improve the referral and treatment algorithms in the high-risk PAD population. FUNDING: None.

Risk stratification and mortality prediction in octo- and nonagenarians with peripheral artery disease: a retrospective analysis.

OBJECTIVES: Among changes in demographics, aging is the most relevant cardiovascular risk factor. The prevalence of peripheral artery disease (PAD) is high in elderly patients and is associated with a worse prognosis. Despite optimal treatments, mortality in the high-risk population of octo- and nonagenarians with PAD remains excessive, and predictive factors need to be identified. The objective of this study was to investigate predictors of mortality in octo- and nonagenarians with PAD. METHODS: Cases of treated octo- and nonagenarians, including the clinical characteristics and markers of myocardial injury and heart failure, were studied retrospectively with respect to all-cause mortality. Hazard ratios [HR] were calculated and survival was analyzed by Kaplan-Meyer curves and receiver operating characteristic curved were assessed for troponin-ultra and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and chronic limb-threatening ischemia (CLTI). RESULTS: A total of 123 octo- and nonagenarians admitted for PAD were eligible. The troponin level was the major predictor of all-cause mortality (HR: 4.6, 95% confidence interval [CI]: 1.4-15.3), followed by the NT-proBNP level (HR: 3.9, 95% CI 1.8-8.8) and CLTI (HR: 3.1, 95% CI 1.6-5.9). Multivariate regression revealed that each increment of 1 standard deviation in log troponin and log NT-proBNP was associated with a 2.7-fold (95% CI 1.8-4.1) and a 1.9-fold (95% CI 1.2-2.9) increased risk of all-cause death. Receiver operating characteristic curve analysis using a combination of all predictors yielded an improved area under the curve of 0.888. In a control group of an equal number of younger individuals, only NT-proBNP (HR: 4.2, 95% CI 1.2-14.1) and CLTI (HR: 6.1, 95% CI 1.6-23.4) were predictive of mortality. CONCLUSION: Our study demonstrates that cardiovascular biomarkers and CLTI are the primary predictors of increased mortality in elderly PAD patients. Further risk stratification through biomarkers in this high-risk population of octo- and nonagenarians with PAD is necessary.

Supervised Exercise Therapy Using Mobile Health Technology in Patients With Peripheral Arterial Disease: Pilot Randomized Controlled Trial.

BACKGROUND: Mobile health interventions are intended to support complex health care needs in chronic diseases digitally, but they are mainly targeted at general health improvement and neglect disease-specific requirements. Therefore, we designed TrackPAD, a smartphone app to support supervised exercise training in patients with peripheral arterial disease. OBJECTIVE: This pilot study aimed to evaluate changes in the 6-minute walking distance (meters) as a primary outcome measure. The secondary outcome measures included changes in physical activity and assessing the patients' peripheral arterial disease-related quality of life. METHODS: This was a pilot two-arm, single-blinded, randomized controlled trial. Patients with symptomatic PAD (Fontaine stage IIa/b) and access to smartphones were eligible. Eligible participants were randomly assigned to the study, with the control group stratified by the distance covered in the 6-minute walking test using the TENALEA software. Participants randomized to the intervention group received usual care and the mobile intervention (TrackPAD) for the follow-up period of 3 months, whereas participants randomized to the control group received routine care only. TrackPAD records the frequency and duration of training sessions and pain levels using manual user input. Clinical outcome data were collected at the baseline and after 3 months via validated tools (the 6-minute walk test and self-reported quality of life). The usability and quality of the app were determined using the Mobile Application Rating Scale user version. RESULTS: The intervention group (n=19) increased their mean 6-minute walking distance (83 meters, SD 72.2), while the control group (n=20) decreased their mean distance after 3 months of follow-up (-38.8 meters, SD 53.7; P=.01). The peripheral arterial disease-related quality of life increased significantly in terms of "symptom perception" and "limitations in physical functioning." Users' feedback showed increased motivation and a changed attitude toward performing supervised exercise training. CONCLUSIONS: Besides the rating providing a valuable support tool for the user group, the mobile intervention TrackPAD was linked to a change in prognosis-relevant outcome measures combined with enhanced coping with the disease. The influence of mobile interventions on long-term prognosis must be evaluated in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04947228; https://clinicaltrials.gov/ct2/show/NCT04947228.

The impact of percutaneous peripheral interventions on endothelial function.

Background: Treatment of symptomatic peripheral artery disease (PAD) through endovascular interventions is the primary revascularization strategy. Interventions restore perfusion but may cause severe injury to the vascular endothelium, which regulates vascular tone. Endothelial dysfunction is involved in the progression of cardiovascular disease, with higher incidences of vascular events. We aimed to determine the impact of percutaneous interventions on change in endothelial function. Patients and methods: Endothelial function was determined using flow-mediated dilation (FMD) before, the day after lower limb intervention with paclitaxel-coated balloons or stent guided interventions and after a six-month follow-up in the target limb, control limb and the systemic circulation in 42 PAD patients aged 70.2±9 years and 66% men. Additionally, macro- and microvascular function were assessed. Results: In PAD patients aged 70.2±9 years and 66% men, we observed an immediate enhancement of macro-, microvascular and endothelial function after endovascular treatment (FMD of superficial femoral artery (SFA) 3.7±0.2% to 4.1±0.1%, n=42, p=0.02), a sustained long-term improvement after 6-months (FMD SFA 3.7±0.2% to 4.2±0.1%, n=42, p=0.01), and moreover an improved systemic endothelial function (FMD brachial artery 4.3±0.1% to 4.7±0.2, n=42, p=0.01) following peripheral interventions. Subgroup analysis however revealed that following paclitaxel-based percutaneous intervention, the paclitaxel dosage applied was inversely related to the chronic improvement in local endothelial function (r=-0.6, n=22, p=0.005) without evidence for systemic effects (r=-0.25, p=0.27). Conclusions: We demonstrate an improved local and systemic endothelial function after treatment of atherosclerotic peripheral disease with a distinguished response after endovascular intervention with higher dosage of applied paclitaxel restraining the benefits. Further studies have to determine the optimal interventional strategy with respect to different treatment modalities to maintain vessel functions.

A Case of Critical Essential Thrombocythemia Complicated by Severe Lower-Extremity Arterial Disease.

BACKGROUND Atherosclerosis and malignancies are leading causes of morbidity and mortality worldwide. In lower-extremity arterial disease (LEAD), progressing or ruptured atherosclerotic plaques are the main culprit for limb ischemia and may cause claudication, chronic wounds, or necrotic lesions. In those cases, standard of care includes revascularization in addition to best medical therapy. Other sources for acute or chronic limb ischemia different from atherosclerosis are often overlooked, especially once atherosclerotic plaques have been detected. CASE REPORT We report the rare case of a patient presenting with painful necrotic ulcerations of the lower extremity due critical essential thrombocythemia that was complicated by an atherosclerotic disease. Based on the clinical presentation, 4 major differential diagnoses were initially considered: Martorell's ulcer, pyoderma gangrenosum, LEAD, and recurrent thromboembolic occlusions due to a malignant disease. Following a thorough, holistic diagnostic work-up, we identified the first diagnosis of critical essential thrombocythemia, which was aggravated by LEAD. CONCLUSIONS This case report highlights the importance of taking malignancies into consideration as a differential diagnosis in patients with repetitive arterial occlusions. With a broad variety of differential diagnoses to be considered for the presented ulcerations, this case report highlights the crucial importance of a rapid interdisciplinary approach to treat and relieve symptoms and prevent further arterial thrombotic events. The learning objective is to give a clear diagnostic work-up to navigate through the most important differential diagnoses of non-atherosclerotic conditions aggravating LEAD.

Impact of Long-term, High-fat, and High-cholesterol Diet on Murine Vertebrae Bones.

As the percentage of overweight individuals in the population rises, diseases associated with excess weight resulting from poor nutrition are becoming more and more widespread. So far, the influence of weight or nutrition on bone health has shown conflicting results. In the literature, the existing studies disagree about the effect of diet on bones. Therefore, this study investigated the impact of a long-term, high-fat, and high-cholesterol diet on the spine in a mouse model. Wild-type mice were randomly separated into two groups; one group received a high-fat and high-cholesterol diet, and a control group was fed with a regular diet since birth for a duration of 8 months. The first to fifth thoracic vertebrae were extracted and investigated using histology and micro-CT. Samples were analyzed regarding different parameters: percentage of bone structure compared to the whole vertebra and the amount and thickness of the trabeculae. Both methods of the analysis showed similar results. Diet did not have a significant impact on the bone density of the vertebrae. The micro-CT examination showed that the average bone percentage of the examined vertebra was 6% (p = 0.2330) higher in the control group compared to the diet group. The same tendency was demonstrated in histology even though with a smaller difference of only 5%. The results of both methods were comparable and showed trends for the influence of different diets but not significant impacts. In summary, this study showed that a high-fat and high-cholesterol diet has a slightly negative impact on bone density. In order to further analyze the effects of different diets on bone composition, structure, and density, additional long-term studies should be carried out, and more parameters such as movement and genetic factors should be analyzed. Furthermore, other parameters such as exercise and genetic factors that could have a secondary influence on obesity should be investigated.

Clinical process optimization of transfemoral transcatheter aortic valve implantation.

Background: The avoidance of prolonged hospital stay is a major goal in the management of transcatheter aortic valve implantation (TAVI) - medically and economically. Materials & methods: We compared the time range of the preprocedural length of stay in 2014/2015 with 2016/2017, after the implementation of the TAVI coordinator in 2016. This included restructured pathways for screening and pre-interventional diagnosis, performed examinations during the inpatient stay and major outcome variables. Results: After 2016, we observed a significant reduction in preprocedural length of stay (admission to procedure) compared with 2014/2015 (11.3 ± 7.9 vs 7.5 ± 5.6 days, p = 0.001). There was no difference in other major outcome variables. Conclusion: The introduction of the TAVI coordinator caused a shortening of preprocedural length of stay.

Radial artery occlusion after cardiac catheterization and impact of medical treatment.

Background: The transradial artery approach is the preferred access for cardiac catheterization according to current guidelines. However, the most common complication is radial artery occlusion (RAO). Despite the rare indication for surgical reopening, the occluded radial artery is not available for further procedures or as a potential bypass graft. Still, treatment regimens for RAO are scarce. We now determined whether the addition of antithrombotic to antiplatelet therapy improves the rate of partial or complete regain of patency in RAO following transradial cardiac catheterization in a retrospective analysis. Patients and methods: In a two-center tertiary referral hospital retrospective analysis 4135 files of patients who had undergone transradial catheterization were screened for documented RAO. 141 patients were identified and 138 patients with complete information on the medical regimen and ultrasound examinations for a maximum of 3 months were included in the analysis, whereas 3 patients were excluded due to missing or incomplete follow-up information. Results: 3.3% of all patients that had undergone transradial catheterization featured an oligosymptomatic RAO, confirmed by color-coded duplex sonography. 21% of patients with additional anticoagulation regained full patency vs. 9% without additional anticoagulation (p = 0.07). 40% of patients with anticoagulation featured a partial or full regain of patency vs. 16% of patients without additional anticoagulation for a maximum of 3 months treatment (p = 0.006). No major bleedings were reported during the follow-up visits. Conclusions: RAO remains a rare complication of cardiac catheterization. The addition of antithrombotic therapy for 3 months appears to safely improve the partial or even full regain of radial patency in case of postinterventional RAO.

Needs and Requirements in the Designing of Mobile Interventions for Patients With Peripheral Arterial Disease: Questionnaire Study.

BACKGROUND: The development of mobile interventions for noncommunicable diseases has increased in recent years. However, there is a dearth of apps for patients with peripheral arterial disease (PAD), who frequently have an impaired ability to walk. OBJECTIVE: Using a patient-centered approach for the development of mobile interventions, we aim to describe the needs and requirements of patients with PAD regarding the overall care situation and the use of mobile interventions to perform supervised exercise therapy (SET). METHODS: A questionnaire survey was conducted in addition to a clinical examination at the vascular outpatient clinic of the West-German Heart and Vascular Center of the University Clinic Essen in Germany. Patients with diagnosed PAD were asked to answer questions on sociodemographic characteristics, PAD-related need for support, satisfaction with their health care situation, smartphone and app use, and requirements for the design of mobile interventions to support SET. RESULTS: Overall, a need for better support of patients with diagnosed PAD was identified. In total, 59.2% (n=180) expressed their desire for more support for their disease. Patients (n=304) had a mean age of 67 years and half of them (n=157, 51.6%) were smartphone users. We noted an interest in smartphone-supported SET, even for people who did not currently use a smartphone. "Information," "feedback," "choosing goals," and "interaction with physicians and therapists" were rated the most relevant components of a potential app. CONCLUSIONS: A need for the support of patients with PAD was determined. This was particularly evident with regard to disease literacy and the performance of SET. Based on a detailed description of patient characteristics, proposals for the design of mobile interventions adapted to the needs and requirements of patients can be derived.

Thymic stromal lymphopoietin is a key cytokine for the immunomodulation of atherogenesis with Freund's adjuvant.

Adaptive immune responses regulate the development of atherosclerosis, with a detrimental effect of type 1 but a protective role of type 2 immune responses. Immunization of Apolipoprotein E-deficient (ApoE-/- ) mice with Freund's adjuvant inhibits the development of atherosclerosis. However, the underlying mechanisms are not fully understood. Thymic stromal lymphopoietin (TSLP) is an IL7-like cytokine with essential impact on type 2 immune responses (Th2). Thymic stromal lymphopoietin is strongly expressed in epithelial cells of the skin, but also in various immune cells following appropriate stimulation. In this study, we investigated whether TSLP may be crucial for the anti-atherogenic effect of Freund's adjuvant. Subcutaneous injection of complete Freund's adjuvant (CFA) rapidly led to the expression of TSLP and IL1ß at the site of injection. In male mice, CFA-induced TSLP occurred in immigrated monocytes-and not epithelial cells-and was dependent on NLRP3 inflammasome activation and IL1ß-signalling. In females, CFA-induced TSLP was independent of IL1ß and upon ovariectomy. CFA/OVA led to a more pronounced imbalance of the T cell response in TSLPR-/- mice, with increased INFγ/IL4 ratio compared with wild-type controls. To test whether TSLP contributes to the anti-atherogenic effects of Freund's adjuvant, we treated ApoE-/- and ApoE-/- /TSLPR-/- mice with either CFA/IFA or PBS. ApoE-/- mice showed less atherogenesis upon CFA/IFA compared with PBS injections. ApoE-/- /TSLPR-/- mice had no attenuation of atherogenesis upon CFA/IFA treatment. Freund's adjuvant executes significant immune-modulating effects via TSLP induction. TSLP-TSLPR signalling is critical for CFA/IFA-mediated attenuation of atherosclerosis.

Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice.

BACKGROUND: Mutations in the human desmin gene (DES) cause autosomal-dominant and -recessive cardiomyopathies, leading to heart failure, arrhythmias, and AV blocks. We analyzed the effects of vascular pressure overload in a patient-mimicking p.R349P desmin knock-in mouse model that harbors the orthologue of the frequent human DES missense mutation p.R350P. METHODS AND RESULTS: Transverse aortic constriction (TAC) was performed on heterozygous (HET) DES-p.R349P mice and wild-type (WT) littermates. Echocardiography demonstrated reduced left ventricular ejection fraction in HET-TAC (WT-sham: 69.5 ± 2.9%, HET-sham: 64.5 ± 4.7%, WT-TAC: 63.5 ± 4.9%, HET-TAC: 55.7 ± 5.4%; p<0.01). Cardiac output was significantly reduced in HET-TAC (WT sham: 13088 ± 2385 µl/min, HET sham: 10391 ± 1349µl/min, WT-TAC: 8097 ± 1903µl/min, HET-TAC: 5793 ± 2517µl/min; p<0.01). Incidence and duration of AV blocks as well as the probability to induce ventricular tachycardias was highest in HET-TAC. We observed reduced mtDNA copy numbers in HET-TAC (WT-sham: 12546 ± 406, HET-sham: 13526 ± 781, WT-TAC: 11155 ± 3315, HET-TAC: 8649 ± 1582; p = 0.025), but no mtDNA deletions. The activity of respiratory chain complexes I and IV showed the greatest reductions in HET-TAC. CONCLUSION: Pressure overload in HET mice aggravated the clinical phenotype of cardiomyopathy and resulted in mitochondrial dysfunction. Preventive avoidance of pressure overload/arterial hypertension in desminopathy patients might represent a crucial therapeutic measure.

Murine sca1/flk1-positive cells are not endothelial progenitor cells, but B2 lymphocytes.

Circulating sca1+/flk1+ cells are hypothesized to be endothelial progenitor cells (EPCs) in mice that contribute to atheroprotection by replacing dysfunctional endothelial cells. Decreased numbers of circulating sca1+/flk1+ cells correlate with increased atherosclerotic lesions and impaired reendothelialization upon electric injury of the common carotid artery. However, legitimate doubts remain about the identity of the putative EPCs and their contribution to endothelial restoration. Hence, our study aimed to establish a phenotype for sca1+/flk1+ cells to gain a better understanding of their role in atherosclerotic disease. In wild-type mice, sca1+/flk1+ cells were mobilized into the peripheral circulation by granulocyte-colony stimulating factor (G-CSF) treatment and this movement correlated with improved endothelial regeneration upon carotid artery injury. Multicolor flow cytometry analysis revealed that sca1+/flk1+ cells predominantly co-expressed surface markers of conventional B cells (B2 cells). In RAG2-deficient mice and upon B2 cell depletion, sca1+/flk1+ cells were fully depleted. In the absence of monocytes, sca1+/flk1+ cell levels were unchanged. A PCR array focused on cell surface markers and next-generation sequencing (NGS) of purified sca1+/flk1+ cells confirmed their phenotype to be predominantly that of B cells. Finally, the depletion of B2 cells, including sca1+/flk1+ cells, in G-CSF-treated wild-type mice partly abolished the endothelial regenerating effect of G-CSF, indicating an atheroprotective role for sca1+/flk1+ B2 cells. In summary, we characterized sca1+/flk1+ cells as a subset of predominantly B2 cells, which are apparently involved in endothelial regeneration.

Pseudoxanthoma elasticum - also a microvascular disease.

Background: Pseudoxanthoma elasticum (PXE) is a heritable recessive disease characterized by calcification and fragmentation of soft connective tissue. Besides progressive loss of vision, alternations of the skin, and early-onset atherosclerosis different reports have suggested a microvascular manifestation of PXE and restrictive lung disease. Aim of this study was to elaborate a specific pattern of capillary alterations in PXE as well as to contemplate a possible connection to restrictive lung disease. Patients and methods: 53 consecutive patients with PXE and 26 controls were studied. All patients underwent nailfold capillaroscopy, body plethysmography, capillary blood gas analysis, and venous puncture to assess titer of autoantibodies. Results: PXE was associated with highly pathological alterations of capillaries compared to control. Atypical capillaries, such as ramifications and bushy forms, as well as dilatations varied at highest significance (p < .001). This effect was mirrored by perivascular edema, density and tortuous capillaries. Titer of anti-nuclear autoantibodies were not elevated in patients with PXE. Further analysis revealed negative correlation between vital capacity and presence of atypical capillaries. Conclusions: This study firstly describes the pattern of nailfold capillaries in PXE. Capillaries are highly pathological and consist of ramifications and bushy forms as well as dilatations. Frequently, tortuous capillaries, pericapillary edema and reduced denseness of capillary loops occur. Frequency of atypical capillaries is negatively correlated with vital capacity which can be interpreted as further lead on restrictive lung disease.

Feasibility and Clinical Relevance of a Mobile Intervention Using TrackPAD to Support Supervised Exercise Therapy in Patients With Peripheral Arterial Disease: Study Protocol for a Randomized Controlled Pilot Trial.

BACKGROUND: Peripheral arterial disease (PAD) is a common and severe disease with a highly increased cardiovascular morbidity and mortality. Through the circulatory disorder and the linked undersupply of oxygen carriers in the lower limbs, the ongoing decrease of the pain-free walking distance occurs with a significant reduction in patients' quality of life. Studies including activity monitoring for patients with PAD are rare and digital support to increase activity via mobile health technologies is mainly targeted at patients with cardiovascular disease in general. The special requirement of patients with PAD is the need to reach a certain pain level to improve the pain-free walking distance. Unfortunately, both poor adherence and availability of institutional resources are major problems in patient-centered care. OBJECTIVE: The objective of this trackPAD pilot study is to evaluate the feasibility of a mobile phone-based self tracking app to promote physical activity and supervised exercise therapy (SET) in particular. We also aim for a subsequent patient centered adjustment of the app prototype based on the results of the app evaluation and process evaluation. METHODS: This study was designed as a closed user group trial, with assessors blinded, and parallel group study with face-to-face components for assessment with a follow-up of 3 months. Patients with symptomatic PAD (Fontaine stage IIa or IIb) and possession of a mobile phone were eligible. Eligible participants were randomly assigned into study and control group, stratified by their distance covered in the 6-min walk test, using the software TENALEA. Participants randomized to the study group received usual care and the mobile intervention (trackPAD) for the follow-up period of 3 months, whereas participants randomized to the control group received only usual care. TrackPAD records the frequency and duration of training sessions and pain level using manual user input. Clinical outcome data were collected at the baseline and after 3 months via validated tools (6-min walk test, ankle-brachial index, and duplex ultrasound at the lower arteries) and self-reported quality of life. Usability and quality of the app was determined using the user version of the Mobile Application Rating Scale. RESULTS: The study enrolled 45 participants with symptomatic PAD (44% male). Of these participants, 21 (47%) were randomized to the study group and 24 (53%) were randomized to the control group. The distance walked in the 6-min walk test was comparable in both groups at baseline (study group: mean 368.1m [SD 77.6] vs control group: mean 394.6m [SD 100.6]). CONCLUSIONS: This is the first trial to test a mobile intervention called trackPAD that was designed especially for patients with PAD. Its results will provide important insights in terms of feasibility, effectiveness, and patient preferences of an app-based mobile intervention supporting SET for the conservative treatment of PAD. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13651.

Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1ß During Dectin-1 Signaling.

Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1ß production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1ß expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP.