Clinical Outcomes of Extracranial Carotid Artery-Related Stroke Eligible for Mechanical Reperfusion on Top of Per-Guidelines Thrombolytic Therapy: Analysis from a 6-Month Consecutive Patient Sample in 2 Centers.

BACKGROUND Systemic intravenous thrombolysis and mechanical thrombectomy (MT) are guideline-recommended reperfusion therapies in large-vessel-occlusion ischemic stroke. However, for acute ischemic stroke of extracranial carotid artery origin (AIS-CA) there have been no specific trials, resulting in a data gap. MATERIAL AND METHODS We evaluated referral/treatment pathways, serial imaging, and neurologic 90-day outcomes in consecutive patients, presenting in a real-life series in 2 stroke centers over a period of 6 months, with AIS-CA eligible for emergency mechanical reperfusion (EMR) on top of thrombolysis as per guideline criteria. RESULTS Of 30 EMR-eligible patients (33.3% in-window for thrombolysis and thrombolysed, 73.3% male, age 39-87 years, median Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 10, pre-stroke mRS 0-1 in all, tandem lesions 26.7%), 20 (66.7%) were EMR-referred (60% - endovascular, 6.7% - surgery referrals). Only 40% received EMR, nearly exclusively in stroke centers with carotid artery stenting (CAS) expertise (100% eligible patient acceptance rate, 100% treatment delivery involving CAS±MT with culprit lesion sequestration using micronet-covered stents). The emergency surgery rate was 0%. Baseline clinical and imaging characteristics did not differ between EMR-treated and EMR-untreated patients. Ninety-day neurologic status was profoundly better in EMR-treated patients: mRS 0-2 (91.7% vs 0%; P<0.001); mRS 3-5 (8.3% vs 88.9%; P<0.001), mRS 6 (0% vs 11.1%; P<0.001). CONCLUSIONS In a real-life AIS-CA setting, the referral rate of EMR-eligible patients for EMR was low, and the treatment rate was even lower. AIS-CA revascularization was delivered predominantly in stroke thrombectomy-capable cardioangiology centers, resulting in overwhelmingly superior patient outcome. Large vessel occlusion stroke referral and management pathways should involve centers with proximal-protected CAS expertise. AIS-CA, irrespective of any thrombolysis administration, is a hyperacute cerebral emergency and EMR-eligible patients should be immediately referred for mechanical reperfusion.

Restenosis is associated with prothrombotic plasma fibrin clot characteristics in endovascularly treated patients with critical limb ischemia.

INTRODUCTION: Hypolysible fibrin clots composed of tightly packed fibers characterize patients with peripheral artery disease (PAD) especially those with critical limb ischemia (CLI). Little is known about the impact of a prothrombotic clot phenotype on restenosis following endovascular revascularization in CLI. The goal of this study was to compare fibrin clot properties and their determinants in CLI patients with restenosis after endovascular treatment (ET) and those free of this complication. METHODS: 85 patients with CLI and restenosis within 1 year after ET on optimal pharmacotherapy and 47 PAD control patients without restenosis were included into the study. Plasma fibrin clot permeability (Ks, a measure of the average pore size in the fibrin network) and clot lysis time (CLT) with its potential determinants were determined. During follow-up, the composite endpoint including re-intervention, amputation and death was assessed. RESULTS: Compared with the control group, patients with restenosis had reduced Ks (- 9.5%, p < 0.001), prolonged CLT (+ 12.4%, p = 0.003), higher thrombin generation (+ 7.9%, p < 0.001) and elevated von Willebrand factor (vWF) antigen (+ 14.2%, p < 0.001). During a 24 months follow-up the composite endpoint occurred in 54 CLI patients with restenosis (63.5%) and nine control patients (19.1%, p < 0.001) with no association with baseline Ks and CLT. CONCLUSION: The increased thrombin formation and unfavorable fibrin clot properties occur in patients with CLI who experienced restenosis despite optimal endovascular and pharmacological therapy.

Atorvastatin and Conditioned Media from Atorvastatin-Treated Human Hematopoietic Stem/Progenitor-Derived Cells Show Proangiogenic Activity In Vitro but Not In Vivo.

Myeloid angiogenic cells (MAC) derive from hematopoietic stem/progenitor cells (HSPCs) that are mobilized from the bone marrow. They home to sites of neovascularization and contribute to angiogenesis by production of paracrine factors. The number and function of proangiogenic cells are impaired in patients with diabetes or cardiovascular diseases. Both conditions can be accompanied by decreased levels of heme oxygenase-1 (HMOX1), cytoprotective, heme-degrading enzyme. Our study is aimed at investigating whether precursors of myeloid angiogenic cells (PACs) treated with known pharmaceuticals would produce media with better proangiogenic activity in vitro and if such media can be used to stimulate blood vessel growth in vivo. We used G-CSF-mobilized CD34+ HSPCs, FACS-sorted from healthy donor peripheral blood mononuclear cells (PBMCs). Sorted cells were predominantly CD133+. CD34+ cells after six days in culture were stimulated with atorvastatin (AT), acetylsalicylic acid (ASA), sulforaphane (SR), resveratrol (RV), or metformin (Met) for 48 h. Conditioned media from such cells were then used to stimulate human aortic endothelial cells (HAoECs) to enhance tube-like structure formation in a Matrigel assay. The only stimulant that enhanced PAC paracrine angiogenic activity was atorvastatin, which also had ability to stabilize endothelial tubes in vitro. On the other hand, the only one that induced heme oxygenase-1 expression was sulforaphane, a known activator of a HMOX1 inducer-NRF2. None of the stimulants changed significantly the levels of 30 cytokines and growth factors tested with the multiplex test. Then, we used atorvastatin-stimulated cells or conditioned media from them in the Matrigel plug in vivo angiogenic assay. Neither AT alone in control media nor conditioned media nor AT-stimulated cells affected numbers of endothelial cells in the plug or plug's vascularization. Concluding, high concentrations of atorvastatin stabilize tubes and enhance the paracrine angiogenic activity of human PAC cells in vitro. However, the effect was not observed in vivo. Therefore, the use of conditioned media from atorvastatin-treated PAC is not a promising therapeutic strategy to enhance angiogenesis.

Involvement of CD8+ T cell subsets in early response to vascular injury in patients with peripheral artery disease in vivo.

AIMS: Adaptive immunity is critical in vascular remodelling following arterial injury. We hypothesized that acute changes in T cells at a percutaneous transluminal angioplasty (PTA) site could serve as an index of their potential interaction with the injured vascular wall. METHODS AND RESULTS: T cell subsets were characterised in 45 patients with Rutherford 3-4 peripheral artery disease (PAD) undergoing PTA. Direct angioplasty catheter blood sampling was performed before and immediately after the procedure. PTA was associated with an acute reduction of α/ß-TcR CD8+ T cells. Further characterisation revealed significant reduction in pro-atherosclerotic CD28nullCD57+ T cells, effector (CD45RA+CCR7-) and effector memory (CD45RA-CCR7-) cells, in addition to cells bearing activation (CD69, CD38) and tissue homing/adhesion markers (CD38, CCR5). CONCLUSIONS: The acute reduction observed here is likely due to the adhesion of cells to the injured vascular wall, suggesting that immunosenescent, activated effector CD8+ cells have a role in the early vascular injury immune response following PTA in PAD patients.

Influence of air pollution on exhaled carbon monoxide levels in smokers and non-smokers. A prospective cross-sectional study.

BACKGROUND: The poor air quality and cigarette smoking are the most important reasons for increased carbon monoxide (CO) level in exhaled air. However, the influence of high air pollution concentration in big cities on the exhaled CO level has not been well studied yet. OBJECTIVES: To evaluate the impact of smoking habit and air pollution in the place of living on the level of CO in exhaled air. METHODS: Citizens from two large cities and one small town in Poland were asked to complete a survey disclosing their place of residence, education level, work status and smoking habits. Subsequently, the CO level in their exhaled air was measured. Air quality data, obtained from the Regional Inspectorates of Environmental Protection, revealed the differences in atmospheric CO concentration between locations. RESULTS: 1226 subjects were divided into 4 groups based on their declared smoking status and place of living. The average CO level in exhaled air was significantly higher in smokers than in non-smokers (p<0.0001) as well as in non-smokers from big cities than non-smokers from small ones (p<0.0001). Created model showed that non-smokers from big cities have odds ratio of 125.3 for exceeding CO cutoff level of 4ppm compared to non-smokers from small towns. CONCLUSIONS: The average CO level in exhaled air is significantly higher in smokers than non-smokers. Among non-smokers, the average exhaled CO level is significantly higher in big city than small town citizens. These results suggest that permanent exposure to an increased concentration of air pollution and cigarette smoking affect the level of exhaled CO.

Costs of Real-Life Endovascular Treatment of Critical Limb Ischemia: Report from Poland-A European Union Country with a Low-Budget Health Care System.

BACKGROUND: To analyze the costs of inhospital, percutaneous treatment of patients with critical limb ischemia (CLI) carried out in Poland, a European Union country with a low-budget national health system. METHODS: A retrospective analysis of prospectively collected data on all patients admitted to a tertiary care hospital for endovascular treatment of CLI over 1 year. SETTING: A single, large volume, tertiary angiology center located in Southern Poland. PARTICIPANTS: CLI patients due to aortoiliac, femoropopliteal, or infrapopliteal arterial stenoses or occlusions with indications for first-line endovascular therapy or similar patients who refused open surgical procedure despite having primary indications for vascular surgery. INTERVENTIONS: Direct stenting using bare-metal stents was the primary mode of treatment for lesions located within the aortoiliac and femoropopliteal arterial segments. Plain old balloon angioplasty (POBA) was the second most commonly used technique. For below-the-knee arteries, POBA was the mainstay of treatment, which was occasionally supported by drug-eluting stent angioplasty. Directional atherectomy, scoring balloon angioplasty, or local fibrinolysis was used infrequently. Drug-eluting balloon percutaneous transluminal angioplasty was not used. MAIN OUTCOME MEASURES: The main outcome measures were the mean reimbursement of costs provided by the Polish National Health Fund (NHF) for inhospital treatment of patients for whom endovascular procedures were performed as initial treatment for CLI and the inhospital costs of endovascular treatment calculated by the caregiver in the 2 years since the first procedure. The average total number of days spent in hospital, amputation-free survival (AFS), overall survival (OS), and limb salvage rate (LSR) according to a life-table method were also calculated for the 2 years. RESULTS: In the first year, there were 496 endovascular and 15 surgical hospitalizations for revascularization procedures to treat 340 limbs in 327 patients, with a further 53 revascularization procedures in the second year. There were an additional 90 hospitalizations over the first year and 38 over the second year for CLI-associated cardiovascular comorbidities. The mean reimbursement for hospitalizations of patients included into observation, provided by the NHF, was $4901.94 per patient for the first year and $833.57 per patient alive to the second year. The mean cost of hospitalization for percutaneous revascularization treatment was $3804.25 per patient for the first year and $3340.30 per patient requiring revascularization within the second year. All costs were calculated in constant 2011 USD. The average total number of days spent in hospital was 8.4 days for the first year and 1.97 days per patient alive to the second year. At 1 and 2 years, the AFS was 76.8% and 66.6%, the OS was 86.5% and 77.3%, and the LSR was 89.4% and 86%, respectively. CONCLUSIONS: Endovascular therapy using the currently available techniques can be performed in almost all patients suffering from CLI at relatively low costs, and satisfactory results can be obtained. Physicians play a pivotal role in ensuring quality of treatment and the reduction of treatment cost in these patients.

Impaired responsiveness to clopidogrel and aspirin in patients with recurrent stent thrombosis following percutaneous intervention for peripheral artery disease.

Patients with peripheral artery disease (PAD) following peripheral percutaneous transluminal angioplasty (PTA) with stent implantation are prone to stent thrombosis despite treatment with aspirin and clopidogrel. Impaired clopidogrel responsiveness is associated with increased risk of ischemic events in patients following coronary stent implantation. We sought to assess platelet responsiveness to clopidogrel and aspirin in patients with PAD and recurrent stent thrombosis. Platelet aggregation induced by 5 and 20 µmol/l adenosine diphosphate (ADP) and 0.5 mmol/l arachidonic acid (AA), together with platelet reactivity index (PRI) and serum thromboxane B(2) (TXB(2)), were determined in 11 patients with PAD and a history of stent thrombosis (mean, 3.1 ± 1.14) after PTA and in 15 patients with PAD with no such history, also in 11 controls with coronary artery disease (CAD) and previous stent thrombosis. Platelet aggregation to 5 µmol/l ADP was higher in subjects with PAD and stent thrombosis than in those without stent thrombosis (p = 0.0003) and CAD subjects (p = 0.002). Aggregation induced by 20 µmol/l ADP was higher in PAD group with stent thrombosis than in PAD subjects without thrombosis (p = 0.004). The PAD group with stent thrombosis had higher AA-induced platelet aggregation than CAD controls (p = 0.007) and serum TXB(2) concentrations higher than PAD group without thrombosis (p = 0.002) and CAD group (p = 0.02). Concluding, platelet responsiveness to clopidogrel and aspirin is impaired in patients with PAD and recurrent stent thrombosis following PTA, as compared with similar individuals with CAD, and PAD with no history of stent thrombosis. This indicates that atherosclerosis burden affects platelet function and might contribute to stent thrombosis following percutaneous intervention in peripheral arteries.

The Influence of Interval Training Combined with Occlusion and Cooling on Selected Indicators of Blood, Muscle Metabolism and Oxidative Stress.

There is increasing evidence to support the use of interval training and/or low-impact blood flow restriction exercises in musculoskeletal rehabilitation. The aim of the study was to assess the effect of interval training combined with occlusion and cooling in terms of changes in selected blood parameters affecting the development and progression of atherosclerosis of the lower limbs, as well as selected parameters of muscle metabolism and oxidative stress affecting the growth of muscle mass and regeneration after training. MATERIAL AND METHODS: The study included 30 young, healthy and untrained people. The VASPER (Vascular Performance) training system was used-High-Intensity Interval Training with the simultaneous use of occlusion and local cryotherapy. Blood from the project participants was collected six times (2 weeks before the start of training, on the day of training, after the first training, after the 10th training, after the 20th training and two weeks after the end of training). The subjects were randomly divided into three groups: exercises only (controlled), with occlusion and with occlusion and local cryotherapy. RESULTS: Statistical analysis of changes in the average values of indicators in all study groups showed a significant change increase due to the time of testing IGF-1 (F = 2.37, p = 0.04), XOD (F = 14.26, p = 0.00), D-Dimer (F = 2.90, p = 0.02), and decrease in MDA (F = 7.14, p = 0.00), T-AOC (F = 11.17, p = 0.00), PT Quick (F = 26.37, p = 0.00), INR (F = 8.79, p = 0.00), TT (F = 3.81, p = 0.00). The most pronounced changes were observed in the occlusion and cooling group. CONCLUSIONS: Both interval training without and with the modifications used in the study influences coagulation and oxidative stress parameters and, to a small extent, muscle metabolism. It seems reasonable to use occlusion and local cryotherapy in combination with occlusion.

World Federation for Interventional Stroke Treatment (WIST) multispecialty training guidelines for endovascular stroke intervention.

Introduction: Today, endovascular treatment (EVT) is the therapy of choice for strokes due to acute large vessel occlusion, irrespective of prior thrombolysis. This necessitates fast, coordinated multi-specialty collaboration. Currently, in most countries, the number of physicians and centres with expertise in EVT is limited. Thus, only a small proportion of eligible patients receive this potentially life-saving therapy, often after significant delays. Hence, there is an unmet need to train a sufficient number of physicians and centres in acute stroke intervention in order to allow widespread and timely access to EVT. Aim: To provide multi-specialty training guidelines for competency, accreditation and certification of centres and physicians in EVT for acute large vessel occlusion strokes. Material and methods: The World Federation for Interventional Stroke Treatment (WIST) consists of experts in the field of endovascular stroke treatment. This interdisciplinary working group developed competency - rather than time-based - guidelines for operator training, taking into consideration trainees' previous skillsets and experience. Existing training concepts from mostly single specialty organizations were analysed and incorporated. Results: The WIST establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in EVT. WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. Conclusions: WIST multispecialty guidelines outline competency and quality standards for physicians and centres to perform safe and effective EVT. The role of quality control and quality assurance is highlighted.

World Federation for Interventional Stroke Treatment (WIST) Multispecialty Training Guidelines for Endovascular Stroke Intervention.

INTRODUCTION: Today, endovascular treatment (EVT) is the therapy of choice for strokes due to acute large vessel occlusion, irrespective of prior thrombolysis. This necessitates fast, coordinated multi-specialty collaboration. Currently, in most countries, the number of physicians and centres with expertise in EVT is limited. Thus, only a small proportion of eligible patients receive this potentially life-saving therapy, often after significant delays. Hence, there is an unmet need to train a sufficient number of physicians and centres in acute stroke intervention in order to allow widespread and timely access to EVT. AIM: To provide multi-specialty training guidelines for competency, accreditation and certification of centres and physicians in EVT for acute large vessel occlusion strokes. MATERIAL AND METHODS: The World Federation for Interventional Stroke Treatment (WIST) consists of experts in the field of endovascular stroke treatment. This interdisciplinary working group developed competency - rather than time-based - guidelines for operator training, taking into consideration trainees' previous skillsets and experience. Existing training concepts from mostly single specialty organizations were analysed and incorporated. RESULTS: The WIST establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in EVT. WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. CONCLUSIONS: WIST multispecialty guidelines outline competency and quality standards for physicians and centres to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. SUMMARY: The World Federation for Interventional Stroke Treatment (WIST) establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in endovascular treatment (EVT). WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. WIST multispecialty guidelines outline competency and quality standards for physicians and centers to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. SIMULTANEOUS PUBLICATION: The WIST 2023 Guidelines are published simultaneously in Europe (Adv Interv Cardiol 2023).

The effect of pain-free treadmill training on fibrinogen, haematocrit, and lipid profile in patients with claudication.

OBJECTIVE: To assess the effect of pain-free treadmill training on changes of plasma fibrinogen, haematocrit, lipid profile, and walking ability in patients with claudication. DESIGN: Randomized control trial. METHODS: Sixty-eight patients with peripheral obstructive arterial disease and intermittent claudication (Fontaine stage II) were randomly assigned into the treadmill training (repetitive intervals to onset of claudication pain, three times a week) or a control group (no change in physical activity) over 3 months. Both groups performed treadmill test to assess pain-free walking time (PFWT) and maximal walking time (MWT) and had blood analyses [for haematocrit, fibrinogen, triglycerides, and cholesterol: total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL)] done at baseline and after 6 and 12 weeks of the study. RESULTS: Total and LDL cholesterol levels in the training group decreased (p < 0.05) by 14.8% and 20,5%, respectively. Significant (p < 0.05) HDL cholesterol increased (14.6%) and triglycerides decreased (19%) in the training group but changes of all these lipids were insignificant in the control group over the 3 months. Haematocrit and fibrinogen changes were insignificant in both groups. PFWT was prolonged by 109% and MWT increased by 54% in the training group (p < 0.01), but not in the control group. CONCLUSION: The improvement in walking time over 3 months of pain-free treadmill training parallels with progressive normalization of lipid profiles in patients with claudication.

Interdisciplinary management of acute ischaemic stroke - current evidence on training requirements for endovascular stroke treatment. Position Paper from the ESC Council on Stroke and the European Association for Percutaneous Cardiovascular Interventions with the support of the European Board of Neurointervention: A step forward.

Stroke, a vascular disease of the brain, is the #1 cause of disability and a major cause of death worldwide. Stroke has a major negative impact on the life of stroke-affected individuals, their families and the society. A significant proportion of stroke victims indicate that would have preferred death over their after-stroke quality of life. Mechanical thrombectomy (MT), opening the occluded artery using mechanical aspiration or a thrombus-entrapment device, is a guideline-mandated (class I, level of evidence A) treatment modality in patients with large vessel occlusion stroke. MT clinical benefit magnitude indicates that a universal access to this treatment strategy should be the standard of care. Today there is a substantial geographic variation in MT deliverability, with large-scale disparities in MT implementation. In many countries effective access to MT remains severely limited. In addition, many of the MT-treated patients are treated too late for a good functional outcome because of logistic delays that include transportations to remotely located, scarce, comprehensive stroke centres. Position Paper from the European Society of Cardiology Council on Stroke and European Association for Percutaneous Cardiovascular Interventions on interdisciplinary management of acute ischaemic stroke, developed with the support of the European Board of Neurointervention fills an important gap in systematically enabling interventional cardiologists to support stroke intervention in the geographic areas of unmet needs in particular. We review strengths and weaknesses of the document, and suggest directions for the next steps that are swiftly needed to deliver MT to stroke patients more effectively.

The relationship between pulse waveform analysis indices, endothelial function and clinical outcomes in patients with peripheral artery disease treated using percutaneous transluminal angioplasty during a one-year follow-up period.

BACKGROUND: Several predictors of clinical outcomes after percutaneous transluminal angioplasty (PTA) interventions in patients with peripheral arterial disease (PAD) have been investigated. Indices of endothelial function, arterial pulse waveform analysis (aPWA) and markers of peripheral artery ischemia were among the most commonly examined. The aim of the current study was to assess the relationship between potential predictors of clinical outcomes after peripheral artery PTA during a 1-year follow-up period. METHODS: The study included 72 individuals with PAD at a mean age of 66.3 ± 7.2 (79.1% males). All patients underwent PTA of the peripheral arteries. Among them, 42.8% presented critical limb ischemia (CLI). During the first visit and at 1 month and 6 months after PTA, endothelial function and aPWA measurements were taken. Ankle-brachial index (ABI), toe-brachial index (TBI) and physical evalu-ation of the limbs took place during the first visit and at 1, 6 and 12 months after the PTA. The study endpoints included myocardial infarction, amputation, death, stroke and reintervention. All subjects included in the study were observed for 386 days after the PTA. RESULTS: A significant improvement was noted in walking distance after PTA at the following time points, as well as transient improvement of ABI and flow-mediated dilatation (FMD) and no significant change in aPWA indices and reactive-hyperaemia index (RHI). The mean ABI, TBI, FMD and RHI values did not correlate with each other at baseline. There were 25 study endpoints which occurred in 16 patients during the follow-up period (22.2%). Patients with CLI, hypercholesterolemia, lower dias-tolic blood pressure, higher subendocardial viability ratio, a greater number of pack-years and lower TBI at baseline presented significantly poorer clinical outcomes in terms of endpoint events. CONCLUSIONS: Endothelial function assessed as FMD and reactive hyperemia-peripheral arterial tonometry (RH-PAT) before PTA in patients with advanced PAD do not predict clinical outcomes during the 1-year follow-up.

miR-378a influences vascularization in skeletal muscles.

AIMS: MicroRNA-378a, highly expressed in skeletal muscles, was demonstrated to affect myoblasts differentiation and to promote tumour angiogenesis. We hypothesized that miR-378a could play a pro-angiogenic role in skeletal muscle and may be involved in regeneration after ischaemic injury in mice. METHODS AND RESULTS: Silencing of miR-378a in murine C2C12 myoblasts did not affect differentiation but impaired their secretory angiogenic potential towards endothelial cells. miR-378a knockout (miR-378a-/-) in mice resulted in a decreased number of CD31-positive blood vessels and arterioles in gastrocnemius muscle. In addition, diminished endothelial sprouting from miR-378a-/- aortic rings was shown. Interestingly, although fibroblast growth factor 1 (Fgf1) expression was decreased in miR-378a-/- muscles, this growth factor did not mediate the angiogenic effects exerted by miR-378a. In vivo, miR-378a knockout did not affect the revascularization of the ischaemic muscles in both normo- and hyperglycaemic mice subjected to femoral artery ligation (FAL). No difference in regenerating muscle fibres was detected between miR-378a-/- and miR-378+/+ mice. miR-378a expression temporarily declined in ischaemic skeletal muscles of miR-378+/+ mice already on Day 3 after FAL. At the same time, in the plasma, the level of miR-378a-3p was enhanced. Similar elevation of miR-378a-3p was reported in the plasma of patients with intermittent claudication in comparison to healthy donors. Local adeno-associated viral vectors-based miR-378a overexpression was enough to improve the revascularization of the ischaemic limb of wild-type mice on Day 7 after FAL, what was not reported after systemic delivery of vectors. In addition, the number of infiltrating CD45+ cells and macrophages (CD45+ CD11b+ F4/80+ Ly6G-) was higher in the ischaemic muscles of miR-378a-/- mice, suggesting an anti-inflammatory action of miR-378a. CONCLUSIONS: Data indicate miR-378a role in the pro-angiogenic effect of myoblasts and vascularization of skeletal muscle. After the ischaemic insult, the anti-angiogenic effect of miR-378a deficiency might be compensated by enhanced inflammation.

From idealistic rookies to a regional leader: the history of health technology assessment in Poland.

In 1989, Poland started to slowly release itself not only from the burden of a half-century of communist indoctrination and soviet exploitation, but also from the consequences of the Semashko model of healthcare organization: low doctors' salaries, primary care based on multispecialty groups, overdeveloped hospital infrastructure, and limited access to sophisticated interventions overcome by patients' unofficial payments. A few years after the 1998 workshop on health technology assessment (HTA) in Budapest, the first HTA reports were elaborated in the National Center for Quality Assessment in Health Care, which could mark the beginning of HTA in Poland. Several individuals and organizations have been involved in developing HTA, both from noncommercial and commercial standpoints. A goal to establish a national HTA agency appeared among the priorities of the Polish Ministry of Health in 2004 and was realized a year later. The Agency for HTA in Poland published guidelines on HTA and established a sound and transparent two-step (assessment-appraisal) process for preparing recommendations on public financing of both drugs and nondrug technologies. The recommendations of the Agency's Consultative Council were warmly welcomed by the public payer. However, the recent major restructuring of the Agency and new drug reimbursement decisions aroused doubts as to keeping transparency of the decision-making processes.

Age-Dependent Impairment in Endothelial Function and Arterial Stiffness in Former High Class Male Athletes Is No Different to That in Men With No History of Physical Training.

Background Physical activity is generally considered to exert positive effects on the cardiovascular system in humans. However, surprisingly little is known about the delayed effect of professional physical training performed at a young age on endothelial function and arterial stiffness in aging athletes. The present study aimed to assess the impact of long-lasting professional physical training (endurance and sprint) performed at a young age on the endothelial function and arterial stiffness reported in older age in relation to glycocalyx injury, prostacyclin and nitric oxide production, inflammation, basal blood lipid profile, and glucose homeostasis. Methods and Results This study involved 94 male subjects with varied training backgrounds, including young athletes (mean age ∼25 years), older former high class athletes (mean age ∼60 years), and aged-matched untrained control groups. Aging increased arterial stiffness, as reflected by an enhancement in pulse wave velocity, augmentation index, and stiffness index (P<10-4), as well as decreased endothelial function, as judged by the attenuation of flow-mediated vasodilation (FMD) in the brachial artery (P=0.03). Surprisingly, no effect of the training performed at a young age on endothelial function and arterial stiffness was observed in the former athletes. Moreover, no effect of training performed at a young age (P>0.05) on blood lipid profile, markers of inflammation, and glycocalyx shedding were observed in the former athletes. Conclusions Our study clearly shows that aging, but not physical training history, represents the main contributing factor responsible for decline in endothelial function and increase in arterial stiffness in former athletes.

Clinical and linguistic validation of the Polish version of VascuQol: a disease-specific quality-of-life questionnaire assessing patients with chronic limb ischemia

INTRODUCTION Objective clinical assessments should include patient­reported outcome measures. VascuQol is an established disease­specific questionnaire assessing the quality of life in patients with peripheral artery disease (PAD). Quality­of­life questionnaires require geographical localization and validation. OBJECTIVES The goal of this study was to validate the Polish version of the VascuQol: a patient­reported health­related quality­of­life (HRQoL) instrument specific for PAD. PATIENTS AND METHODS The linguistic validation of VascuQol followed Mapi Institute methodology. Clinical validation process compared VascuQol, EQ­5D­3L, and SF­36 questionnaires in 100 patients with both intermittent claudication and critical limb­threatening ischemia. Cronbach α coefficients for reliability, receiver operating characteristic curves for clinical discriminative performance, standardized response means for responsiveness, and Pearson correlations for construct validity were evaluated. Additionally, in a separate cohort of 58 patients with stable disease, the test­retest was characterized with intraclass correlation, Bland­Altman analysis, and Pearson correlation coefficients. RESULTS VascuQol proved to perform better than SF­36 and EQ­5D­3L. Cronbach α coefficients showed good internal consistency (α values >0.9 for all summary scores). All test­retest Pearson r values for VascuQol were above 0.70. The intraclass correlation of absolute agreement consistency exceeded 0.8. The Bland­Altman 95% limits of agreement were between 2.72 and 4.87. There were strong and moderate correlations for total scores in all domains between VascuQol and SF­36, and for most of the domains between VascuQol and EQ­5D­3L. CONCLUSIONS The Polish version of VascuQol is a sensitive, accurate, and reliable tool for assessing HRQoL in patients with PAD.

[Thrombotic thrombocytopenic purpura with myocardial ischaemia: two case reports]. / Zakrzepowa plamica maloplytkowa z objawami niedokrwienia miesnia sercowego--opis dwóch przypadków.

Thrombotic thrombocytopenic purpura (TTP) is mainly perceived by cardiologists as a rare complication of ticlopidine or clopidogrel treatment. However, this life-threatening disease is provoked not only by antiplatelet drugs and may lead to myocardial ischaemia and necrosis caused by microvascular thrombosis and anaemia. We present two thienopiridine-naive patients who had acquired TTP and myocardial ischaemia, and were successfully treated by plasma exchanges.

Antithrombotic effects of aspirin based on PLA1/A2 glycoprotein IIIa polymorphism in patients with coronary artery disease.

OBJECTIVE: The diallelic glycoprotein IIIa polymorphism P1A1/A2 was attributed to be an inherited risk factor for coronary events. Whether this polymorphism affects response to aspirin in patients with coronary artery disease is not known. METHODS: We assessed thrombin generation (prothrombin fragment F1+2) in consecutive blood samples collected from bleeding-time wounds in 28 men with coronary artery disease; P1A2 carriers, n=9; P1A1/A1, n=19. Thrombin generation and bleeding time were measured before and after 2 weeks of aspirin 300 mg/day. RESULTS: Aspirin-depressed thrombin generation in A1 homozygotes (p=0.04), but not in A2 carriers. Bleeding time after aspirin was also prolonged in A1 subjects only (p=0.02). CONCLUSION: Genotyping for glycoprotein IIIa polymorphism might be helpful in predicting antithrombotic action of aspirin in secondary prevention of coronary artery disease.

Soluble endoglin as a prognostic factor of the claudication distance improvement in patients with peripheral artery disease undergoing supervised treadmill training program.

Conservative therapy after complete revascularization is increasing in popularity in patients with peripheral artery disease (PAD). The aim of the present study was to find determinants of the improvement of walking abilities and endothelial function in patients with PAD undergoing supervised treadmill training program (STTP). The presented study enclosed 66 patients in the mean age 65.4 ± 7.7 years with PAD who underwent a 3-month length STTP. We assessed the effect of following factors on the change of the flow-mediated dilatation value (ΔFMD), maximal walking time (ΔMWT), and pain-free walking time (ΔPFWT). The evaluation included several biochemical and anthropometric indices with special insight into markers of angiogenesis, including soluble endoglin (sEng), platelet-derived growth factor, and angiopoietin-2. Linear regression analysis for each of the variables and multi-factorial model analysis of variances was adopted to select the most influential determinants. The levels of sEng, a biomarker of several cardiovascular pathologies, were found to significantly predict the greater improvement of maximal walking time and pain-free walking time. Moreover, the linear regression analysis demonstrated, and analysis of variance confirmed that coronary artery disease and peracted endovascular interventions of lower limbs arteries are significant determinants of the better ΔFMD improvement. On the contrary, treatment with ß-blockers and older age were poor predictors of ΔFMD increase. In conclusion, the sEng level could serve as a determinant of walking abilities change after STTP in patients with PAD. The treatment with ß-blockers, the coexistence of coronary artery disease, and peracted endovascular interventions of lower limbs arteries are determinants of endothelial function.