Search

Summary: The optimal first line management of patients with symptomatic chronic lower extremity peripheral artery disease (PAD) includes secondary prevention of cardiovascular risk factors, pharmacological treatment, and supervised exercise therapy (SET). SET programs have shown to be effective in improving walking performance, functional performance, and quality of life. However, despite a large body of evidence, and despite national and international guidelines recommending SET as first line therapy, SET remains largely underused in patients with chronic PAD. This position paper aims to describe how SET is perceived, its accessibility and structure through Europe. An anonymous web-based survey was used. It comprised 21 questions developed in conjunction with an angiologist and a clinical exercise physiologist specialist in vascular rehabilitation. We had 131 responders from 17 countries. For patients with PAD, SET programs exist only in 59% of European countries. SET reimbursement is available in 41% of countries. SET programs showed to be heterogeneous across countries. Thirty-four percent of the SET programs are PAD-dedicated, while 23% are part of a cardiac rehabilitation program. In addition, among existing SET programs, 65% are dedicated to symptomatic patients with PAD only, 9% to both asymptomatic and symptomatic, 8% to post-revascularized patients only, and 1% to asymptomatic patients with PAD only. Finally, 17% reported not knowing which patients are eligible for enrolment in a SET program. Duration, frequency, and modality of SET also varied from country to country. Overall, these data indicate that a large variability of SET availability and characteristics exists across Europe. Therefore, there is an urgent need to provide detailed guidance to deliver optimal exercise therapeutic care in patients with PAD.

Summary: With an increasing global burden of patients with chronic peripheral artery disease (PAD) the safe and effective provision of lower limb revascularisation is a growing medical need. Endovascular procedures for the treatment of PAD have become a crucial cornerstone of modern vascular medicine, and the first line revascularisation approach if technically feasible and taking patient choice into consideration. With the increasing age of patients with PAD and the increasing number of comorbidities open vascular surgery is also often not feasible. We outline a framework of key messages, endorsed by the board of the European Society of Vascular Medicine for pre-, peri- and post procedural management of patients requiring endovascular arterial procedures of the lower limbs. These key messages emphasize the important and increasing role of interventional vascular physicians.

Summary: Post-thrombotic syndrome (PTS) is a chronic venous insufficiency manifestation following an episode of deep-vein thrombosis (DVT). It is an important and frequent long-term adverse event of proximal DVT affecting 20–50% of patients. This position paper integrates data guiding clinicians in deciding PTS diagnosis, treatment and follow-up.

Summary: Background: Peripheral artery disease (PAD) of the lower limbs is a common condition with considerable global burden. Some country-specific studies suggest low levels of public awareness. To our knowledge public awareness of PAD has never been assessed simultaneously in several countries worldwide. Patients and methods: This was an international, general public, internet-based quantitative survey assessing vascular health and disease understanding. Questionnaires included 23 closed-ended multiple-choice, Likert scale and binary choice questions. Data were collected from 9,098 survey respondents from nine countries in Europe, North and Latin America during May-June 2018. Results: Overall, familiarity with PAD was low (57% of respondents were “not at all familiar”, and 9% were “moderately” or “very familiar”). Knowledge about PAD health consequences was limited, with 55% of all respondents not being aware of limb consequences of PAD. There were disparities in PAD familiarity levels between countries; highest levels of self-reported awareness were in Germany and Poland where 13% reported to be “very” or “moderately” familiar with PAD, and lowest in Scandinavian countries (5%, 3% and 2% of respondents in Norway, Sweden and Denmark, respectively). There were disparities in awareness according to age. Respondents aged 25–34 were most familiar with PAD, with 12% stating that they were “moderately” or “very” familiar with the condition, whereas those aged 18–24 were the least familiar with PAD (7% “moderately” or “very” familiar with PAD). In the 45–54, 55–64 and 65+ age groups, 9% said they were “moderately” or “very” familiar with the term. There was no important gender-based difference in PAD familiarity. Conclusions: On an international level, public self-reported PAD awareness is low, even though PAD is a common condition with considerable burden. Campaigns to increase PAD awareness are needed to reduce delays in diagnosis and to motivate people to control PAD risk factors.

Background: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described. Methods: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization. Results: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71–1.01) with clopidogrel and 0.86 (95% CI, 0.73–1.01) without clopidogrel without statistical heterogeneity ( P for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14–1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22–1.01] without clopidogrel; P for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use ( P for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44–7.13]) compared with shorter durations of clopidogrel ( P for trend=0.06). Conclusions: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02504216.

Abdominal aortic aneurysms (AAA) are a significant cause of premature deaths worldwide. Since there is no specific treatment for reducing AAA progression, it is crucial to understand the pathogenesis leading to aneurysm wall weakening/remodeling and identify new proteins involved in this process which could subsequently serve as novel therapeutic targets. In this study, we analyzed the presence of the hypoxia-related proteins carbonic anhydrase IX (CA IX), hypoxia-inducible factor 1α (HIF-1α), and AKT as the key molecule in the phosphoinositide-3-kinase pathway in the AAA wall. Additionally, we used a blood-based assay to examine soluble CA IX (s-CA IX) levels in the plasma of AAA patients. Using western blotting, we detected CA IX protein in 12 out of 15 AAA tissue samples. Immunohistochemistry staining proved CA IX expression in the media of the aneurysmal wall. Evaluation of phosphorylated (p-AKT) and total AKT showed elevated levels of both forms in AAA compared to normal aorta. Using ELISA, we determined the concentration of s-CA IX >20 pg/mL in 13 out of 15 AAA patients. Results obtained from in silico analysis of CA9 and aneurysm-associated genes suggest a role for CA IX in aneurysmal wall remodeling. Our results prove the presence of hypoxia-related CA IX in AAA tissues and indicate a possible role of CA IX in hypoxia-associated cardiovascular diseases.

Low attention has generally been dedicated to the influence of clinical presentation, extent of venous thrombosis and presence of residual vein obstruction (RVO) on the decision about the duration of secondary prophylaxis after a first venous thromboembolism (VTE).This study aimed at investigating the role of the mentioned VTE characteristics on the therapeutic decision using the information collected in the international, prospective, observational WHITE study.1240 patients were recruited by 79 clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). 35 patients had as index event a pulmonary embolism (PE) without a deep vein thrombosis (DVT), and all continued anticoagulation. We focused on the 1205 subjects with DVT. The treatment decision differed among countries; altogether, more than 85% of patients with proximal (with or without distal) DVT continued a prophylactic treatment with anticoagulants, or antithrombotics; 34% of patients with isolated distal DVT stopped treatment, and more than 85% of patients with a PE associated to a DVT continued treatment. At multivariable analysis, the presence of proximal DVT, signs of post-thrombotic syndrome (PTS), residual vein obstruction (RVO), maintenance180 days and concomitant diseases was associated with increased probability to continue secondary prophylaxis.The presentation as proximal DVT (with or without PE) or isolated PE influenced the treating physicians' decision in favor of extension of secondary prophylaxis, together with the presence of concomitant diseases and local conditions which may increase the risk of post-thrombotic syndrome.

The decision on treatment after a first venous thromboembolism (VTE) to prevent recurrences may be influenced by many factors. The prospective, observational, WHITE study aimed to analyze how this issue was tackled in every-day clinical practice in various countries, which have sensibly different socio-economic conditions and healthcare systems. Doctors active in 79 Internal or Vascular clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia) enrolled VTE patients after the maintenance treatment phase. The present report analyzed information, collected in the central database, regarding the baseline characteristics, index events, type and duration of anticoagulant therapy and decision on post-maintenance treatment. From April 2018 to December 2020, 1240 patients were enrolled, 58% with an unprovoked index event. Direct oral anticoagulants (DOACs) were used in > 85% of all cases in China, Poland, Portugal, Russia and Czechia, in 52% in Slovakia and in no patient in Tunisia. The maintenance anticoagulation lasted in average approximately 6 months. Altogether, anticoagulation was stopped in 20%, extended in about 50%, regardless of whether the event was unprovoked or provoked and shifted to antithrombotics (mainly sulodexide or aspirin) in the remaining patients. In conclusion, some differences in VTE patient management were found between countries. The provoked/unprovoked nature of the index event, instead, was not the prevalent criterion to drive the decision on extension of anticoagulation, without large variations between countries. DOACs were the most widely used anticoagulant drugs, whereas > 25% of patients received antithrombotic drugs instead of anticoagulants as extended treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s11739-021-02765-1.

(1) Background: The treatment of peripheral arterial disease (PAD) is focused on improving perfusion and oxygenation in the affected limb. Standard revascularization methods include bypass surgery, endovascular interventional procedures, or hybrid revascularization. Cell-based therapy can be an alternative strategy for patients with no-option critical limb ischemia who are not eligible for endovascular or surgical procedures. (2) Aims: The aim of this narrative review was to provide an up-to-date critical overview of the knowledge and evidence-based medicine data on the position of cell therapy in the treatment of PAD. The current evidence on the cell-based therapy is summarized and future perspectives outlined, emphasizing the potential of exosomal cell-free approaches in patients with critical limb ischemia. (3) Methods: Cochrane and PubMed databases were searched for keywords "critical limb ischemia and cell therapy". In total, 589 papers were identified, 11 of which were reviews and 11 were meta-analyses. These were used as the primary source of information, using cross-referencing for identification of additional papers. (4) Results: Meta-analyses focusing on cell therapy in PAD treatment confirm significantly greater odds of limb salvage in the first year after the cell therapy administration. Reported odds ratio estimates of preventing amputation being mostly in the region 1.6-3, although with a prolonged observation period, it seems that the odds ratio can grow even further. The odds of wound healing were at least two times higher when compared with the standard conservative therapy. Secondary endpoints of the available meta-analyses are also included in this review. Improvement of perfusion and oxygenation parameters in the affected limb, pain regression, and claudication interval prolongation are discussed. (5) Conclusions: The available evidence-based medicine data show that this technique is safe, associated with minimum complications or adverse events, and effective. Web of Science 21 23 art. no. 8999

Abstract. Regarding the clinical diagnosis of Raynaud’s phenomenon and its associated conditions, investigations and treatment are substantial, and yet no international consensus has been published regarding the medical management of patients presenting with this condition. Most knowledge on this topic derives from epidemiological surveys and observational studies; few randomized studies are available, almost all relating to drug treatment, and thus these guidelines were developed as an expert consensus document to aid in the diagnosis and management of Raynaud’s phenomenon. This consensus document starts with a clarification about the definition and terminology of Raynaud’s phenomenon and covers the differential and aetiological diagnoses as well as the symptomatic treatment.

Background Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, acts as an inhibitor of angiogenesis and is associated with an increased risk of cardiovascular mortality. Administration of stem cells may affect endogenous mechanisms that regulate ADMA production and metabolism. The aim of the present study was to analyze ADMA concentration and changes in oxidative stress in patients with advanced critical limb ischemia (CLI) after bone marrow-derived mononuclear cell (BM-MNC) therapy. Methods Fifty patients (age 64 ± 11 years, 44 males, 6 females) with advanced CLI (Rutherford category 5 or 6) not eligible for revascularization were treated by intramuscular (n = 25) or intra-arterial (n = 25) injection of 40 ml BM-MNC concentrate. Patients with limb salvage and improved wound healing after 6 months were considered responders to cell therapy. The concentrations of markers of oxidative stress and angiogenesis were analyzed before, and at 3 and 6 months after BM-MNC delivery. Results At 6-month follow-up, four patients died of reasons unrelated to stem cell therapy. Among the survivors, 80% (37/46) showed limb salvage and improved wound healing. At 6 months follow-up, ADMA concentration significantly decreased in patients with limb salvage (1.74 ± 0.66 to 0.90 ± 0.49 μmol/L, p

Abstract. Chronic critical lower limb ischemia (CLI) has been defined as ischemia that endangers the leg. An attempt was made to give a precise definition of CLI, based on clinical and hemodynamic data (Second European Consensus). CLI may be easily defined from a clinical point of view as rest pain of the distal foot or gangrene or ulceration. It is probably useful to add leg ulcers of other origin which do not heal because of severe ischemia, and to consider the impact of frailty on adverse outcome. From a hemodynamic viewpoint there is no consensus and most of the existing classifications are not based upon evidence. We should thus propose a definition and then validate it in a prospective cohort in order to define the patients at major risk of amputation, and also to define the categories of patients whose prognosis is improved by revascularisation. From today’s available data, it seems clear that the patients with a systolic toe pressure (STP) below 30 mmHg must be revascularised whenever possible. However other patients with clinically suspected CLI and STP above 30 mmHg must be evaluated and treated in specialised vascular units and revascularisation has to be discussed on a case by case basis, taking into account other data such as the WiFi classification for ulcers.In conclusion, many useful but at times contradictory definitions of CLI have been suggested. Only a few have taken into account evidence, and none have been validated prospectively. This paper aims to address this and to give notice that a CLI registry within Europe will be set up to prospectively validate, or not, the previous and suggested definitions of CLI.

International audience

Background International guidelines recommend at least three months anticoagulation in all patients after acute venous thromboembolism (VTE) and suggest those with unprovoked events be considered for indefinite anticoagulation if the risk of recurrence is high and the risk of bleeding during treatment non-high. Other authors have recently argued against using a dichotomy unprovoked/provoked events to decide on anticoagulation duration and suggest instead using overall risk factors present in each patient as the basis for deciding. Aim This sub-analysis of the WHITE study aimed at assessing the reasons for the treatment decisions taken by doctors in different countries. Results 1240 patients were recruited in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). Anticoagulation was extended in 51.7% and 49.3% of patients with unprovoked or provoked events (n.s.); stopped in 15.4% versus 28.9% ( P 83% of cases) given to continue anticoagulation, regardless of nature and site of the index events, followed by risk of bleeding and presence of PTS signs. Conclusion On average, attending physicians estimated the risk of recurrence in real life conditions, and the consequent therapeutic decision, using all the information available, not limiting to the location or nature of the index event.

Background Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease. Methods In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months. Results The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49). Conclusions In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .).

Background The present study investigated factors associated with therapeutic benefits after autologous bone marrow cell (BMC) therapy in patients with “no-option” critical limb ischemia (CLI). Methods and results Sixty-two patients with advanced CLI (Rutherford category 5 or 6) not eligible for revascularization were randomized to treatment with 40 ml of autologous BMCs (SmartPreP2) by local intramuscular (n = 32) or intra-arterial (n = 30) application. The primary endpoint was limb salvage and wound healing at 12 months. Seven patients (11 %) died during the follow-up from reasons unrelated to stem cell therapy. The BMC product of patients with limb salvage and wound healing (33/55) was characterized by a higher CD34+ cell count (p = 0.001), as well as a higher number of total bone marrow mononuclear cells (BM-MNCs) (p = 0.032), than that of nonresponders (22/55). Patients with limb salvage and wound healing were younger (p = 0.028), had lower C-reactive protein levels (p = 0.038), and had higher transcutaneous oxygen pressure (tcpO2) (p = 0.003) before cell application than nonresponders. All patients with major tissue loss at baseline (Rutherford 6 stage of CLI, n = 5) showed progression of limb ischemia and required major limb amputation. In the multiple binary logistic regression model, the number of applied CD34+ cells (p = 0.046) and baseline tcpO2 (p = 0.031) were independent predictors of limb salvage and wound healing. The number of administrated BM-MNCs strongly correlated with decreased peripheral leukocyte count after 6 months in surviving patients with limb salvage (p = 0.0008). Conclusion Patients who benefited from autologous BMC therapy for “no-option” CLI were treated with high doses of CD34+ cells. The absolute number of applied BM-MNCs correlated with the improvement of inflammation. We hypothesize that the therapeutic benefit of cell therapy for peripheral artery disease is the result of synergistic effects mediated by a mixture of active cells with regenerative potential. Patients at the most advanced stage of CLI do not appear to be suitable candidates for cell therapy. Trial registration The study was approved and registered by the ISRCTN registry. Trial registration: ISRCTN16096154. Registered: 26 July 2016.

Stem cell therapy has been proposed to be an alternative therapy in patients with critical limb ischemia (CLI), not eligible for endovascular or surgical revascularization. We compared the therapeutic effects of intramuscular (IM) and intra-arterial (IA) delivery of bone marrow cells (BMCs) and investigated the factors associated with therapeutic benefits. Forty-one patients (mean age, 66 ± 10 years; 35 males) with advanced CLI (Rutherford category, 5 and 6) not eligible for revascularization were randomized to treatment with 40 ml BMCs using local IM ( n = 21) or selective IA infusion ( n = 20). Primary endpoints were limb salvage and wound healing. Secondary endpoints were changes in transcutaneous oxygen pressure (tcpO2), quality-of-life questionnaire (EQ5D), ankle–brachial index (ABI), and pain scale (0–10). Patients with limb salvage and wound healing were considered to be responders to BMC therapy. At 6-month follow-up, overall limb salvage was 73% (27/37) and 10 subjects underwent major amputation. Four patients died unrelated to stem cell therapy. There was significant improvement in tcpO2(15 ± 10 to 29 ± 13 mmHg, p < 0.001), pain scale (4.4 ± 2.6 to 0.9 ± 1.4, p < 0.001), and EQ5D (51 ± 15 to 70 ± 13, p < 0.001) and a significant decrease in the Rutherford category of CLI (5.0 ± 0.2 to 4.3 ± 1.6, p < 0.01). There were no differences among functional parameters in patients undergoing IM versus IA delivery. Responders ( n = 27) were characterized by higher CD34+cell counts in the bone marrow concentrate (CD34+29 ± 15×106vs. 17 ± 12×106, p < 0.05) despite a similar number of total nucleated cells (4.3 ± 1.4×109vs. 4.1 ± 1.2×109, p = 0.66) and by a lower level of C-reactive protein (18 ± 28 vs. 100 ± 96 mg/L, p < 0.05) as well as serum leukocytes (8.3 ± 2.1×109/L vs. 12.3 ± 4.5×109/L, p < 0.05) as compared with nonresponders (10 patients). Both IM and IA delivery of autologous stem cells are effective therapeutic strategies in patients with CLI. A higher concentration of CD34+cells and a lower degree of inflammation are associated with better clinical therapeutic responses.

Induction of therapeutic angiogenesis by autologous bone marrow mononuclear cell transplantation has been identified as a potential new option in patients with advanced lower-limb ischemia. There is little evidence of the benefit of intra-arterial cell application in upper-limb critical ischemia. We describe a patient with upper-extremity critical limb ischemia with digital gangrene resulting from hypothenar hammer syndrome successfully treated by intra-arterial autologous bone marrow mononuclear cell transplantation.

Background Despite their controversial effect, "renal" doses of dopamine (3-5 microg kg(-1) min(-1)) are often used in intensive care units to preserve renal function and to improve final outcome. Aim To assess the effects of different doses of dopamine on renal blood flow in patients with normal renal function and in patients with renal dysfunction. Methods and results In 17 patients with normal renal function and in 12 patients with moderate renal dysfunction, mean arterial pressure (MAP), heart rate (HR), and average peak renal flow velocities (FlowWire APV) were continuously recorded at baseline and during IV administration of increasing dopamine doses (3, 5, 10, 20, and 30 microg kg(-1) min(-1)). MAP and HR did not change during infusion of 3-5 microg kg(-1) min(-1) but increased to the same extent in both groups during infusion of >10 microg kg(-1) min(-1). Baseline APV was similar in both groups. Infusion of 3-5 mug . kg(-1) . min(-1) induced a significant change in APV only in patients with normal renal function. In patients with renal dysfunction, APV increased only during infusion of >10 microg kg(-1) min(-1) in parallel with MAP and HR. Conclusion "Renal" doses of dopamine increase renal blood flow in normals but not in patients with moderate renal dysfunction.

Aims To assess the accuracy of tissue Doppler imaging-derived myocardial positive pre-ejection velocity (+Vic) in detecting myocardial viability defined by dobutamine stress echocardiography (DSE), fluorine-18 fluorodeoxyglucose positron emission tomography (PET), and contrast-enhanced magnetic resonance imaging (MRI), and in predicting recovery of left ventricular (LV) function after coronary artery bypass grafting (CABG) in patients with chronic ischaemic LV dysfunction. Methods and results +Vic in dysfunctional segments was recorded in 54 patients treated medically and 65 patients undergoing CABG [age 67 ± 9 year; LV ejection fraction (EF) 30 ± 6%]. A good agreement was observed between +Vic and detection of viable myocardium at DSE, PET, and MRI (kappa = 0.76). The presence of +Vic in greater than or equal to five dysfunctional segments had the highest sensitivity (93%) and specificity (60%) to identify patients ( n = 28) with ≥10% increase in LV EF between baseline and 6-month echocardiogram. During follow-up (median 333 days, interquartile range 209–490 days), 13 cardiac events (6 deaths, 7 hospitalizations) occurred in 24 patients with small extent of viable myocardium (< 5 + Vic), whereas only four hospitalizations in 39 patients with ≥5 + Vic (54% vs. 10%; P < 0.001). Conclusion The extent of +Vic in dysfunctional segments accurately predicts extent of viable myocardium and bears a clinical prognostic value in patients with ischaemic LV dysfunction considered for CABG.

Aims Exercise-induced mitral regurgitation (MR) bears a poor prognosis in patients with congestive heart failure (CHF). Cardiac resynchronization therapy (CRT) is associated with improved clinical outcome but its effects on exercise-induced MR remain undetermined. We investigated serial changes in functional MR in relation to left ventricular (LV) remodelling and cardiopulmonary performance after CRT. Methods and results Twenty-eight patients with CHF (LV ejection fraction 25 ± 7%), broad QRS complex (171 ± 27 ms), and at least mild MR [effective regurgitant orifice (ERO) 0.25 ± 0.12 cm2] were studied with quantitative exercise echocardiography and cardiopulmonary exercise testing prior, within 1 week, and 3 months after CRT. Early after CRT, a decrease in LV dyssynchrony (from 54 ± 21 to 19 ± 7 ms, P < 0.001) and in MR at rest (ERO from 0.25 ± 0.12 to 0.20 ± 0.10 cm2, P = 0.047) was observed. However, no change in exercise-induced increase in MR was observed (ERO from 0.34 ± 0.12 to 0.31 ± 0.16 cm2, NS). Three months after CRT, a decrease in the mitral valve tenting area (from 3.3 ± 1.2 to 2.0 ± 0.6 cm2, P < 0.001) and an increase in LV sphericity index (from 1.5 ± 0.3 to 1.8 ± 0.5, P < 0.001) were paralleled by an attenuation of exercise-induced MR (ERO 0.19 ± 0.06 cm2, P = 0.001 vs. prior CRT). This was associated with an increase in LV ejection fraction (from 25 ± 7 to 35 ± 9%, P < 0.001), peak oxygen uptake (from 11.7 ± 2.4 to 13.7 ± 3.8 mL/kg/min, P = 0.001), and a decrease in Nt-pro-BNP (from 2777 ± 1681 to 1963 ± 1361 pg/mL, P = 0.067). Conclusion CRT is associated with acute decrease in resting MR but does not immediately attenuate exercise-induced MR. In contrast, only late, CRT-induced reversed LV remodelling and reduced mitral apparatus deformation are associated with a reduction in both resting and exercise-induced MR and with an improvement in cardiopulmonary performance.

Objectives: The purpose of this study was to define "significant" renal artery stenosis (i.e., a stenosis able to induce arterial hypertension). Background: The degree of renal artery stenosis that justifies an attempt at revascularization is unknown. Methods: In 15 patients, transstenotic pressure measurements were obtained before and after unilateral stenting. After stenting, graded stenoses were created in the stented segment by progressive inflation of a balloon catheter. Stenosis severity was expressed as the ratio of distal pressure (Pd) corrected for aortic pressure (Pa). Balloon inflation pressure was adjusted to create 6° of stenosis (Pd/Pa from 1.0 to 0.5, each step during 10 min). Plasma renin concentration was measured at the end of each step in the aorta and in both renal veins. Results: For a Pd/Pa ratio >0.90, no significant change in plasma renin concentration was observed. However, when Pd/Pa became d/Pa of 0.50 (p = 0.006). These values returned to baseline when the stenosis was relieved. In addition, plasma renin concentration increased significantly in the vein from the non-stenotic kidney (p = 0.02). Conclusions: In renal artery stenoses, a Pd/Pa ratio of 0.90 can be considered a threshold value below which the stenosis is likely responsible for an up-regulation of renin production and, thus, for renovascular hypertension. These findings might contribute to better patient selection for renal angioplasty.

Objective: The study investigated the impact of renal sympathetic denervation on office blood pressure and ambulatory blood pressure monitoring in patients with resistant hypertension. We evaluated whether a decrease in blood pressure may improve local carotid stiffness and parameters of wave intensity. Methods: Renal sympathetic denervation was performed in 17 patients (age 55 ± 9 years) with true resistant hypertension. Measurements of carotid stiffness and wave intensity were performed using ultrasound combined with echo-tracking. Results: We found significantly improved office systolic blood pressure changes 1 month (p=0.023) and together with pulse pressure changes at the 6 month follow up (p=0.041; p=0.016). Changes in systolic blood pressure during the daytime were significantly decreased at 1 month and diastolic blood pressure changes during the daytime were significantly reduced at 1 and 3 months. Stiffness parameters beta stiffness and pressure-strain elastic modulus were significantly reduced (p=0.04; p=0.03) and arterial compliance was increased (p=0.03), especially 1 and 3 months. The changes in negative area were significantly reduced after 1 month (p=0.041) and the ejection period was significantly increased at the 6 month follow-up (p=0.011). According to linear regression analysis systolic blood pressure correlated positively with the beta stiffness, pressure-strain elastic modulus, pulse wave velocity, and negatively with arterial compliance. Conclusions: We found significantly lower office blood pressure as well as blood pressure from ambulatory blood pressure monitoring in patients with resistant hypertension 6 months after renal sympathetic denervation. The decrease in blood pressure was followed by improvement of carotid stiffness and wave intensity. That may be reflected in enhancement of ventricular-arterial coupling.

Vascular complications after lumbar laminectomy are rare, but are potentially life-threatening. A 59-year-old man presented with progressive and worsening abdominal pain over several weeks. Multidetector computed tomography angiography revealed a large aorto-ostial left renal artery pseudoaneurysm 3 years after lumbar laminectomy. The pseudoaneurysm was successfully treated with a combination of various endovascular techniques ("jailed" microcatheter technique, stent-graft implantation, thrombin injection, balloon remodeling technique, Onyx application), with preserved patency of the left renal artery and pseudoaneurysm exclusion on 6-month follow-up multidetector computed tomography angiography. The size and location of this pseudoaneurysm and the combination of different techniques for endovascular treatment provides an update on current endovascular technology. Combination of different endovascular techniques can be a safe and feasible alternative for the treatment of complicated iatrogenic postlaminectomy vascular injuries and renal artery pseudoaneurysms.

Aims: To evaluate efficacy of percutaneous ultrasound-guided thrombin injection (UGTI) of iatrogenic femoral artery pseudoaneurysm (PSA) and to identify the risk factors associated with PSA recurrence. Methods and results: We treated 140 patients aged 76 years (range 49-83) presented with femoral artery PSA after cardiac catheterisation by percutaneous UGTI (500 IU/ml solution of activated human thrombin). Factors associated with the recurrence of PSA were analysed. One hundred nineteen patients were successfully treated by one injection of thrombin (immediate success rate 85%). In 19 patients (13.6%), short local compression following injection was needed for complete occlusion (overall success rate 98.6%, 138/140). In one case, progression of PSA required conversion to surgery (0.7%). In one patient with pre-existing stenosis of superficial femoral artery, acute limb ischaemia developed after UGTI (0.7%). The recurrence of PSA in 30-days follow-up (10 patients, 7%) was associated with obesity (BMI>30, OR=1.39, 95% Cl 1.09-1.78, p

Aims: A ratio of distal renal pressure to aortic pressure (P d/Pa) angio), minimal luminal diameter (MLD), Doppler-derived peak systolic velocity (PSV), end-diastolic velocity (EDV), and renal-to-aortic ratio (RAR) were obtained and compared with the Pd/Pa measured with a 0.014" pressure wire. Pd/Pa correlated with angiography- and CDUS-derived parameters. The best correlation was observed with EDV (R = -0.61). To identify stenosis associated with a P d/Pa < 0.90, the diagnostic accuracy of DS angio > 50%, MLD < 2 mm, PSV > 180 cm/s, EDV > 90 cm/s and RAR > 3.5 were, respectively, 60%, 77%, 45%, 77% and 79%, yet, with a high proportion of false positives (38%, 15%, 55%, 11% and 15%, respectively) indicating an overestimation of the severity of the RAS by both QRA and CDUS. New cut-off values for QRA- and CDUS-derived indices were proposed. Conclusion: Generally accepted QRA and CDUS-derived indices of RAS severity overestimate the actual severity of RAS. This 'overdiagnosis' is likely the main cause of the disappointing results of renal angioplasty for renovascular hypertension.

Background: Cardiac resynchronization therapy (CRT) leads to better cardiopulmonary performance in congestive heart failure (CHF) patients (pts). Mechanisms underlying the benefits are not fully elucidated. Aim: To investigate factors and mechanisms associated with improved cardiopulmonary performance after CRT. Methods: Twenty-three pts (EF 26±7%, QRS complex 170±26 msec) were studied by simultaneous quantitative semi-supine exercise echocardiography and cardiopulmonary exercise testing before and 3 months after CRT. Pts with an increase (Δ) in peak VO 2 ≥1.1 ml/kg/min were considered clinical responderes. Effective regurgitant orifice (ERO) of the mitral regurgitation (MR) was assessed using the PISA method. Results: In the entire population, CRT was associated with a decrease in LV dyssynchrony from 53±2 to 23±9 msec (p2 (p2 increased from 11.6±2.3 to 12.9±3.6 ml/kg/min (p ), ERO at rest was similar but exercise-induced ERO and Nt-pro BNP were significantly lower in responders vs nonresponders. Change in peak VO 2 correlated inversely with the extent of exercise-induced MR at follow-up (r=−0.47, p Conclusions. Improved cardiopulmonary performance after CRT is related to changes in exercise-induced MR rather than resting MR. Thus, effects on the exercise-induced MR in parallel to reverse LV remodelling appear to contribute to improved cardiopulmonary performance and clinical benefits of the CRT.

Background The left internal mammary artery (LIMA) is the conduit of choice for revascularization of coronary arteries and its popularity further increases in the era of mini-invasive coronary surgery. The aim of this study was first, to assess the accuracy of CDUS in predicting the LIMA graft dysfunction as compared to angiography, and secondly, to correlate the postoperative status of the LIMA graft with preoperative coronary artery stenosis severity of the bridged lesion. Methods and results We examined 111 patients (pts) by colour-duplex ultrasound after myocardial revascularization by LIMA bypass (3.8 ± 3.2 years after revascularization). LIMA was detected from the left supraclavicular approach at rest using the 7.5 MHz linear transducer. The ultrasound results were compared to contemporaneous angiography. The LIMA bypass patency was correlated with the preoperative coronary artery stenosis severity. The LIMA was detected by ultrasound in 92.8% (103) pts. At angiography, LIMA was patent and functional in 85 pts (76.6%, group A); in 25 subjects LIMA was stenosed or dysfunctional (22.5%, group B). In one patient the coronary subclavian steal syndrome was detected (0.9%). Haemodynamically moderate stenosis (50–60% by preoperative quantitative coronary angiography) was grafted in 5 pts of group A (6%), but in 10 pts of group B (40%) ( P < 0.0001 vs group A). A peak systolic to peak diastolic velocity ratio (SDVR) of

The aim of the study was to quantify the changes in cardiopulmonary function after minimally invasive video-assisted mitral valve repair for organic mitral regurgitation (MR) in asymptomatic or minimally symptomatic patients.Twenty-six patients (age 54 +/- 11 years) with severe organic MR (regurgitant volume of 94 +/- 37 mL, effective regurgitant orifice [ERO] of 0.73 +/- 0.35 cm2) and mild or no symptoms (New York Heart Association class 1.2 +/- 0.4) underwent exercise echocardiography and cardiopulmonary exercise testing 1 week before and 4 months after uncomplicated video-assisted mitral valve repair.During exercise, left ventricular ejection fraction increased from 68% +/- 7% to 74% +/- 6% (P.0001), but ERO did not change significantly. Four months after video-assisted mitral valve repair, a significant improvement was observed in peak oxygen uptake (VO2max from 23 +/- 6 to 25 +/- 7 mL x kg(-1) x min(-1), P.001), peak oxygen pulse (11 +/- 3 to 12 +/- 4 mL per beat, P.005) as well as in maximal workload (from 143 +/- 49 to 159 +/- 55 W, P.0001). When only patients without any symptoms (New York Heart Association class I, n = 20) were considered, these changes were even more pronounced (VO2max from 24 +/- 7 to 27 +/- 7 mL x kg(-1) x min(-1), P.001). Post-operative changes in VO2max correlated with preoperative exercise-induced contractile reserve (r = 0.72, P.0001), preoperative ERO (r = 0.49, P.05), and preoperative ejection fraction at rest (r = 0.42, P.05).In patients with severe organic MR but mild or no symptoms, cardiopulmonary performance improves after successful minimally invasive video-assisted mitral valve repair. Improvement is directly related to preoperative left ventricular function and contractile reserve.

OBJECTIVES: The purpose of this work was to establish the normal range of maximal renal hyperemic response in humans and to identify the ideal renal vasodilatory stimuli. BACKGROUND: Stenotic renovascular atherosclerosis is increasingly treated by percutaneous transluminal renal intervention but with an unpredictable outcome. This may be due to hemodynamically non-significant stenosis or the presence of irreversible damage to the glomerular circulation. We propose that the renovascular hyperemic response may help identify appropriate patients. METHODS: In 28 normotensive patients, quantitative angiographic measurements of the renal artery were obtained, and renal artery pressure and flow velocity were continuously recorded after various hyperemic agents. RESULTS: In a first group of 11 patients, a significant increase in renal artery average peak velocity (APV) was observed after intrarenal (IR) bolus injection of 600 μg isosorbide dinitrate (41 ± 19%), 30 mg papaverine (50 ± 34%), 50 μg dopamine (94 ± 54%), 0.8 μg·kg-1 fenoldopam (80 ± 25%), and during IR infusion of 1 μg·kg-1·min-1 fenoldopam (86 ± 28%). A second group of 17 patients received intravenous infusion of dopamine (3, 5, 10, 20, 30, and 40 μg·kg -1·min-1). The 3 and 5 μg·kg -1·min-1 of dopamine modestly reduced renal resistance index (RI) (-13 ± 15% and -25 ± 20%, respectively). At higher dosages, no further decline in RI was observed. No significant change in vessel diameter was observed before and after the administration of the pharmacological stimuli suggesting that changes in APV corresponded with changes in absolute renal blood flow. CONCLUSIONS: The normal renal flow reserve averages approximately 2 in humans with normal renal function. An IR bolus injection of 50 μg·kg-1 of dopamine is the most convenient means to elicit maximal renal hyperemia.

Using B-mode ultrasound, we studied the prevalence of abdominal aortic aneurysm (AAA; diameteror =3 cm) and its predictive risk factors in 109 consecutive patients who were60 years of age and had coronary artery disease (CAD). A group of 60 age-matched patients who did not have CAD served as controls. The prevalence of AAA was higher in the CAD group than in the control group (14%, 16 of 109, vs 3%, 2 of 60, p0.05). By multivariate analysis, only smoking was strongly associated with AAA (odds ratio 4.86, 95% confidence interval 1.55 to 15.25). In contrast, presence of diabetes mellitus was negatively associated with AAA in univariate analysis (odds ratio 0.11, 95% confidence interval 0.01 to 0.83) and a strong trend of inverse association remained in multivariate analysis (odds ratio 0.12, 95% confidence interval 0.01 to 1.03). Thus, systematic screening can detect AAA in 1 of 7 patients who are60 years of age and have CAD. AAA shares some, but not all, risk factors of atherosclerosis.

Acute transplant renal artery thrombosis is a rare complication in kidney transplantation that often leads to renal allograft loss. We present the first case of acute renal artery thrombosis 3 months after kidney transplantation, treated with pharmacomechanical thrombectomy with adjunctive catheter-directed thrombolysis and stent placement. The graft was salvaged with restoration of renal function and renal artery patency at the 3-year follow-up point.

Objective: Carotenoids and flavonoids are both plants origin and have a well described anti-oxidant activity. Recently we demonstrated the protective effect of carotenoids on endothelial cells. In the current study we aimed to evaluate the possible synergistic activity of these substances as anti-oxidant and anti inflammatory mediators on endothelial cells. Methods: Endothelial cells (EA.hy926) were pre-incubated with vehicle, lycopen, dissolved chocolate, epicatechin solution, combination of lycopen with chocolate and combination of lycopen with epicatechin solution for 18-24h. After incubation, stable oxidized products of NO examined. In another assay pre incubated cells with the above substances were induced with TNF-a for 6h. The activated cells were examined for protein abundance of: eNOs, adhesion molecules ICAM-1, VCAM-1 and osteopontin (OPN). Results: There was a significant augmentation of NOx production after pre incubation with each substance separately. Moreover, the combination of lycopen with either chocolate or epicatechin resulted in synergistic effect. Lycopen with chocolate 8.1 5.1 (OD) and lycopen with epicatechin 6.9 2.3 (OD), versus control 1.4 1.2 (OD) and lycopen 2.3 0.9 (OD) respectively (p

BackgroundApplication of autologous bone marrow mononuclear cells to "no option" patients with advanced critical limb ischemia (CLI) prevented major limb amputation in 73% patients during the 6-month follow-up. We examined which properties of bone marrow stromal cells also known as bone-marrow derived mesenchymal stem cells of responding and non-responding patients are important for amputation-free survival.Methods and findingsMesenchymal stem cells of 41 patients with CLI unsuitable for revascularisation were isolated from mononuclear bone marrow concentrate used for their treatment. Based on the clinical outcome of the treatment, we divided patients into two groups: responders and non-responders. Biological properties of responders' and non-responders' mesenchymal stem cells were characterized according to their ability to multiply, to differentiate in vitro, quantitative expression of cell surface markers, secretion of 27 cytokines, chemokines and growth factors, and to the relative expression of 15 mesenchymal stem cells important genes. Secretome comparison between responders (n=27) and non-responders (n=14) revealed significantly higher secretion values of IL-4, IL-6 and MIP-1b in the group of responders. The expression of cell markers CD44 and CD90 in mesenchymal stem cells from responders was significantly higher compared to non-responders (pConclusionsThe quality of mesenchymal stem cells shown in the expression of cell surface markers, secreted factors and stem cell genes plays an important role in therapeutic outcome. Paracrine mechanisms are main drivers in the induction of reparatory processes in CLI patients. Differences in mesenchymal stem cells properties are discussed in relation to their involvement in the reparatory process.

Endovascular abdominal aortic aneurysm repair (EVAR) is accepted therapeutic strategy. The use of a total percutaneous approach to endovascular repair of aortic pathology is becoming more common and further extends the EVAR indications. The aim of our retrospective analysis was assessment of safety

Abstract 2999 Introduction: Autologous bone marrow cell application has been proposed as an alternative therapy in patients (pts) with critical limb ischemia (CLI), not eligible for endovascular or surgical revascularization, but the way of their administration is currently unresolved. The aim of our study is to compare intramuscular (i.m.) and intraarterial (i.a.) bone marrow blood (BMB) delivery. Methods: Fifty nine patients (median age 67 years, range 38 – 89; gender M :F = 50 :9) with advanced CLI (Rutherford category 5, 6) not eligible for revascularization underwent analgosedation with profolol and total of 240 ml of BMB from both posterior iliac crests were harvested and stabilized with heparin. Bone marrow aspirate was processed with SmartPreP2 Bone Marrow Aspirate Concentrate System (Harvest, Plymouth, MA) – gradient density centrifugation to provide 40 ml of BMB concentrate (BMBc) within 15–20 minutes. Patients were randomized to treatment with 40 ml of BMBc either using local i.m. or i.a. infusion. Primary end points were limb salvage and wound healing. Secondary end points included changes in transcutaneous oxygen pressure (tcpO2), quality of life questionnaire (EQ 5D), ankle-brachial index (ABI), and pain scale (0–10 scale). Patients with limb salvage and wound healing were considered as responders to BMBc therapy. Results: Fifty nine collected BMB contained median mononucleated cell number 35, 8 × 109/l (range 12, 5 – 79, 8) and CD34+ cells 237, 25 × 106/l (range 57, 2 – 694, 3). Processing of BMB reduced to volume from 240 ml to 40 ml (e.g. 6x) and increased concentration of mononucleated cells and CD34+ cells (2, 9x). According to the randomization BMBc was administered i.m. (24 patients) into the ischemic limb or by means of i.a. infusion (800ml/hour) through the catheter positioned into the popliteal artery (25 patients). Since procedure 41 patients could reach 180 days follow up, 4 patients died from unrelated reason to study and 37 patients were evaluable for response. Twenty seven of 37 had limb salvage (73%). There was significant improvement in tcpO2 (15±10 to 29±13mmHg, p Conclusions: Autologous bone marrow blood harvest and administration is safe. There is no difference in i.m. versus i.a. application, both methods of autologous BMB delivery are effective in pts with CLI. Higher CD34+ cell content in BMBc and lower degree of inflammation are associated with good response to BMB application. Funding of project “Transplantation of autologous bone-marrow stem cells in patients with critical limb ischemia” ITMS code 26240220023 is supported by Operational programme Research and Innovation from European Regional Development Fund. Disclosures: No relevant conflicts of interest to declare.