Cilostazol for peripheral arterial disease - a position paper from the Italian Society for Angiology and Vascular Medicine.

Cilostazol is a quinolinone-derivative selective phosphodiesterase inhibitor and is a platelet-aggregation inhibitor and arterial vasodilator for the symptomatic treatment of intermittent claudication (IC). Cilostazol has been shown to improve walking distance for patients with moderate to severe disabling intermittent claudication who do not respond to exercise therapy and who are not candidates for vascular surgical or endovascular procedures. Several studies evaluated the pharmacological effects of cilostazol for restenosis prevention and indicated a possible effect on re-endothelialization mediated by hepatocyte growth factor and endothelial precursor cells, as well as inhibiting smooth muscle cell proliferation and leukocyte adhesion to endothelium, thereby exerting an anti-inflammatory effect. These effects may suggest a potential effectiveness of cilostazol in preventing restenosis and promoting the long-term outcome of revascularization interventions. This review aimed to point out the role of cilostazol in treating patients with peripheral arterial disease, particularly with IC, and to explore its possible role in restenosis after lower limb revascularization.

Current Opinion on Diagnosis of Peripheral Artery Disease in Diabetic Patients.

Peripheral arterial disease (PAD) prevalence and diabetes mellitus (DM) prevalence are continuously increasing worldwide. The strong relationship between DM and PAD is highlighted by recent evidence. PAD diagnosis in diabetic patients is very important, particularly in patients with diabetic foot disease (DFD); however, it is often made difficult by the characteristics of such diseases. Diagnosing PAD makes it possible to identify patients at a very high cardiovascular risk who require intensive treatment in terms of risk factor modification and medical therapy. The purpose of this review is to discuss the diagnostic methods that allow for a diagnosis of PAD in diabetic patients. Non-invasive tests that address PAD diagnosis will be discussed, such as the ankle-brachial index (ABI), toe pressure (TP), and transcutaneous oxygen pressure (TcPO2). Furthermore, imaging methods, such as duplex ultrasound (DUS), computed tomography angiography (CTA), magnetic resonance angiography (MRA), and digital subtraction angiography (DSA), are described because they allow for diagnosing the anatomical localization and severity of artery stenosis or occlusion in PAD. Non-invasive tests will also be discussed in terms of their ability to assess foot perfusion. Foot perfusion assessment is crucial in the diagnosis of critical limb ischemia (CLI), the most advanced PAD stage, particularly in DFD patients. The impacts of PAD diagnosis and CLI identification in diabetic patients are clinically relevant to prevent amputation and mortality.

Common Practice in the Treatment of Superficial Vein Thrombosis Involving the Sapheno-Femoral Junction: Results from a National Survey of the Italian Society of Angiology and Vascular Medicine (SIAPAV).

Background and Objectives: Prophylactic doses of low-molecular-weight heparins or fondaparinux showed their efficacy and safety for treatment of all superficial vein thrombosis (SVT) of the lower limbs, yet not for those extended to the last 3 cm of the great saphenous vein, close to the sapheno-femoral junction, or considered as a deep-vein thrombosis. Some experts suggest that these patients should be managed with full anticoagulant doses but evidence to support this recommendation is lacking, suggesting the need for a properly designed trial. Materials and Methods: Before starting a new trial, the Italian Society of Angiology and Vascular Medicine (SIAPAV) decided to verify the common therapeutic approaches for patients with an SVT in Italian vascular centers based on a hypothetical significant variation in each daily clinical practice. A standardized questionnaire of 10 questions was administered to all SIAPAV affiliates by means of the official Society website. Results: From 1 December 2022 to 20 January 2023 a total of 191 members (31.8%) answered the questionnaire, showing a detailed and a substantial heterogeneity in the therapeutic approach to SVT patients among experienced vascular physicians and angiologists. Detailed results are reported in the relative section. Conclusions: The therapeutic approach of SVT extended to the iuxta-femoral segment of the great saphenous vein is still a matter of debate, and data to support therapeutic strategies are lacking. The wide heterogeneity in the management of SVT patients, including those with more extended thrombosis, confirmed that a randomized controlled clinical trial investigating the efficacy and the safety of a tailored therapeutic regimen in this particular subgroup of patients is strongly warranted.

Treatment of Superficial Vein Thrombosis: Recent Advances, Unmet Needs and Future Directions.

Once considered relatively benign, superficial vein thrombosis (SVT) of the lower limbs is linked to deep vein thrombosis (DVT) or pulmonary embolism (PE) in up to one fourth of cases. Treatment goals include alleviating local symptoms and preventing SVT from recurring or extending into DVT or PE. Fondaparinux 2.5 mg once daily for 45 days is the treatment of choice for most patients with SVT. Potential alternatives include intermediate-dose low-molecular-weight heparin or the direct oral factor Xa inhibitor rivaroxaban, however, these require further evidence. Despite these treatment options, significant gaps remain, including the role of systemic or topical anti-inflammatory agents alone or combined with anticoagulants, and the optimal duration of anticoagulation for patients at varying risk levels. Additionally, the efficacy and safety of factor Xa inhibitors other than rivaroxaban, management of upper extremity SVT, and optimal treatment for SVT near the sapheno-femoral or sapheno-popliteal junctions are not well understood. This narrative review aims to summarize current evidence on anticoagulant treatment for SVT, highlight key unmet needs in current approaches, and discuss how ongoing studies may address these gaps.

Guidelines on the diagnosis, treatment and management of visceral and renal arteries aneurysms: a joint assessment by the Italian Societies of Vascular and Endovascular Surgery (SICVE) and Medical and Interventional Radiology (SIRM).

The objective of these Guidelines is to provide recommendations for the classification, indication, treatment and management of patients suffering from aneurysmal pathology of the visceral and renal arteries. The methodology applied was the GRADE-SIGN version, and followed the instructions of the AGREE quality of reporting checklist. Clinical questions, structured according to the PICO (Population, Intervention, Comparator, Outcome) model, were formulated, and systematic literature reviews were carried out according to them. Selected articles were evaluated through specific methodological checklists. Considered Judgments were compiled for each clinical question in which the characteristics of the body of available evidence were evaluated in order to establish recommendations. Overall, 79 clinical practice recommendations were proposed. Indications for treatment and therapeutic options were discussed for each arterial district, as well as follow-up and medical management, in both candidate patients for conservative therapy and patients who underwent treatment. The recommendations provided by these guidelines simplify and improve decision-making processes and diagnostic-therapeutic pathways of patients with visceral and renal arteries aneurysms. Their widespread use is recommended.

Special Issue "Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations 2022".

This Special Issue, titled "Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations", aims to demonstrate recent and new advances and future trends in the field of rheumatic diseases [...].

Amputation rate and mortality in elderly patients with critical limb ischemia not suitable for revascularization.

In spite of recent progress in revascularization and anesthesiology procedures, in vascular centers today there are still patients with Critical Limb Ischemia (CLI) who are not considered suitable for revascularization. Most of these patients are elderly, with high co-morbidity factors, poor run off arterial limb vessels, and often with a salvageable limb. They are absent or neglected in the literature, and generally go untreated. We report details of 24- month amputations and mortality rates in 90 patients with CLI who were not considered suitable for revascularization, treated from 2005 to 2008 in a dedicated unit of our department. Patients with endstage general conditions or needing immediate primary amputation were excluded from our study. All patients received multidisciplinary assessment. Their median age was 78.4 years; 28 patients (31.1%) had rest pain only, and 62 (68.8%) had ischemic skin foot-leg wounds or gangrene <2 cm. Sixteen patients (37.7%) were assessed as not suitable for revascularization because of poor functional status, and 76 (64.4%) because of inadequate outflow limb vessels. Drugs to manage pain were administered to all patients (100%), prostanoid infusions were given to 80 (88%), anti-platelet drugs to 87 (96%), low molecular weight heparin or oral anticoagulants to 13 (14%), spinal cord stimulation to 3 (3%), hyperbaric oxygen treatment to 16 (17%) and wound treatment to 62 (68.8%). Toe or other foot-sparing amputations had a rate of 13%. After 24 months, the major amputation rate was 9.3% and the mortality rate 23.2%. Our observations show that, in spite of progress in revascularization procedures, there are still patients with CLI who are not considered suitable for revascularization and who could benefit from non-surgical treatment if a tailored approach is used.

PBMNCs Treatment in Critical Limb Ischemia and Candidate Biomarkers of Efficacy.

When in critical limb ischemia (CLI) the healing process aborts or does not follow an orderly and timely sequence, a chronic vascular wound develops. The latter is major problem today, as their epidemiology is continuously increasing due to the aging population and a growth in the incidence of the underlying diseases. In the US, the mean annualized prevalence of necrotic wounds due to the fact of CLI is 1.33% (95% CI, 1.32-1.34%), and the cost of dressings alone has been estimated at USD 5 billion per year from healthcare budgets. A promising cell treatment in wound healing is the local injection of peripheral blood mononuclear cells (PBMNCs). The treatment is aimed to induce angiogenesis as well to switch inflammatory macrophages, called the M1 phenotype, into anti-inflammatory macrophages, called M2, a phenotype devoted to tissue repair. This mechanism is called polarization and is a critical step for the healing of all human tissues. Regarding the clinical efficacy of PBMNCs, the level of evidence is still low, and a considerable effort is necessary for completing the translational process toward the patient bed site. From this point of view, it is crucial to identify some candidate biomarkers to detect the switching process from M1 to M2 in response to the cell treatment.

Current opinion on the role of the foot perfusion in limb amputation risk assessment.

The most important and consulted guidelines dealing with not healing foot ulcers suggest the measurement of the foot perfusion (FP) to exclude the critical limb ischemia (CLI), because of the high risk of limb amputation. But the recommended cut-off values of FP fail to include all the heterogeneity of patients of the real-life with a not healing ulcer. Often these patients are diabetics with a moderate PAD but with a high level of infection. To meet this goal, in 2014, the Society for Vascular Surgery has published the "Lower Extremity Threatened Limb Classification System: Risk stratification based on Wound, Infection, and foot Ischemia (WIfI)." This new classification system has changed the criteria of assessment of limb amputation risk, replacing the single cut-off value role with a combination of a spectrum of perfusion values along with graded infection and dimension levels of skin ulcers. The impact of this new classification system was remarkable so to propose the substitution of the CLI definition, with the new Critical limb-threatening ischemia (CLTI), that seems to define the limb amputation risk more realistically.

The compelling arguments for the need of microvascular investigation in COVID-19 critical patients.

The burden of pandemic COVID-19 is growing worldwide, as the continuous increases of contagion. Only 10-15% of the entire infected population has the necessity of intensive care unit (ICU) treatments. But, this relatively low rate of patients has absorbed almost the whole availability of ICU during few days, becoming at least in Italy, an emergency for the national health system. In COVID-19 ICU patients massive aggression of lung with severe pulmonary failure, as well as kidney and liver injuries, heart, brain, bowel and spleen damages with lymph nodes necrosis and even cutaneous manifestations have been observed. Moreover, increased levels of cytokines so-called "cytokines storm (CS), and overt intravascular disseminated coagulation have been also reported. The hypercoagulation and CS would speculate about a microvascular dysfunction. Unfortunately, no specific observations have been performed on microcirculatory dysfunction in COVID-19 patients. Hence the presumed pathophysiological pathways and models about a microvascular involvement can be gathered by sepsis models studies. But despite this lack of evidence, the COVID-19 has emphasized the compelling need for microcirculation monitoring at the bedside in ICU patients.

COVID-19 Sepsis and Microcirculation Dysfunction.

The spreading of Coronavirus (SARS-CoV-2) pandemic, known as COVID-19, has caused a great number of fatalities all around the World. Up to date (2020 May 6) in Italy we had more than 28,000 deaths, while there were more than 205.000 infected. The majority of patients affected by COVID-19 complained only slight symptoms: fatigue, myalgia or cough, but more than 15% of Chinese patients progressed into severe complications, with acute respiratory distress syndrome (ARDS), needing intensive treatment. We tried to summarize data reported in the last months from several Countries, highlighting that COVID-19 was characterized by cytokine storm (CS) and endothelial dysfunction in severely ill patients, where the progression of the disease was fast and fatal. Endothelial dysfunction was the fundamental mechanism triggering a pro-coagulant state, finally evolving into intravascular disseminated coagulation, causing embolization of several organs and consequent multiorgan failure (MOF). The Italian Society of Clinical Hemorheology and Microcirculation was aimed to highlight the role of microcirculatory dysfunction in the pathogenetic mechanisms of COVID-19 during the spreading of the biggest challenges to the World Health.

Current opinions about the definition of critical limb ischemia: A debate still open after three decades.

Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease. It is clinically defined as rest pain with or without skin ulcer or gangrene and carries a very poor prognosis with a high rates of limb amputation and cardiovascular mortality. Despite the first definition of CLI has been published more than 30 years ago, the debate about what it really is, is still open. Over the years the hemodynamic parameters utilised to define the critical level of limb perfusion have changed. This has raised some question about the apparent confusion about the definition of CLI. Moreover, a new term such as "limb threatening ischemia" has replaced the definition of CLI in recent guideline. Therefore, it becomes necessary to understand the evolution of the concept and the definition of CLI, to interpret the future trend.Hence, this work analysing the guideline documents on peripheral arterial disease that have defined the CLI to date, aims to clarify the path that has brought to the current conceptual changes of the definition of CLI.

Bridging the gap between basic research on microcirculation and clinical world: The translational marriage between engineering and medicine.

The words "Translational" and "Medicine" have been recently coupled to indicate a combination of disciplines, resources, expertise, and techniques aimed at enhancing prevention, diagnosis, and therapies. As stated in 2015 by the European Society for Translational Medicine, translational medicine is "an interdisciplinary branch of the biomedical field supported by three main pillars: benchside, bedside and community". By definition, Translational Medicine is a highly interdisciplinary field, which gathers several specialties aimed at improving the global healthcare system.With regard to the assessment of the microcirculatory function, it is worthwhile to mention the growing interest from both basic research and clinical practice. Microcirculation is where the exchange of substances between blood and tissues takes place. Thus, it plays a key role in the pathophysiology of many diseases. Nonetheless, a gap does exist between the theoretical analysis of the microcirculatory function and its clinical exploitation. This gap can be due to the weak dissemination of analytical methods and theoretical results within the clinical community, which also delays the establishment of specific operative guidelines.This paper aims at encouraging, and possibly accelerating, the translation of basic research outcomes on microcirculatory function assessment into clinical applications.

Trends of the treatment of Critical Limb Ischemia during the last two decades.

In this review 14 studies were identified reporting the treatment strategy in 4891 patients with Critical Limb Ischemia (CLI) with the aim to investigate if the strategy of treatment of the first episode of CLI has changed during the last 15-20 years. A computer research has been performed on PubMed and Scopus databases on November 2016. The used terms for the investigation about studies evaluating the strategy of treatment of CLI at the first-time presentation, have been "critical leg ischemia", "critical limb ischemia", "critical lower limb ischemia" along with the terms "placebo", "medical treatment" and/or "conservative" revascularisation, surgical revascularisation, endovascular revascularisation, hybrid revascularisation and primary amputation. Studies were included if they were either retrospective or prospective and reporting the rate of patients who underwent to any form of revascularization, conservative treatment and primary amputation. The one-year limb and life survival rates have been reported as major outcomes. The pooled rate of revascularization was 72.5% (95% CI 80-64.96) of which 54.5%, surgical, 38.3% endovascular and 7.1% hybrid. The bivariate regression of revascularisation procedures has been with not significant increase, from 68% in 1993 to 88% in 2015. The endovascular procedures have shown a significant increase of the trend, from 2% to more the 50% (p 0.007), while surgical and hybrid procedures have not. The pooled rate of conservative treatment was 18% (95% CI 11.6-24.5%) with a not significant increasing trend and primary amputation pooled rate was 8.7% (95% CI 12.0-5,4) with a significant decreasing trend (p 0.009). The one-year limb survival rate was 75,4% (95% CI 81.5-69.3%) and the life survival was 76%. (95% CI 85.4-66.1%) both with a not significant increasing trend. In conclusion, this review highlights how the treatment strategy of the first CLI manifestation has changed over the last 15-20 years. It has shown an increase of the rate of revascularization procedures, particularly for endovascular and a significant reduction of the rate of primary amputations. The rate of patients treated conservatively appears to be unchanged and maybe influencing the rate of limb and life survival, that have remained unchanged.

The wavelet analysis for the assessment of microvascular function with the laser Doppler fluxmetry over the last 20 years. Looking for hidden informations.

The wavelet analysis has been applied to the Laser Doppler Fluxmetry for assessing the frequency spectrum of the flowmotion to study the microvascular function waves.Although the application of wavelet analysis has allowed a detailed evaluation of the microvascular function, its use does not seem to be yet widespread over the last two decades.Aiming to improve the diffusion of this methodology, we herein present a systematic review of the literature about the application of the wavelet analysis to the laser Doppler fluxmetry signal. A computer research has been performed on PubMed and Scopus databases from January 1990 to December 2017. The used terms for the investigation have been "wavelet analysis", "wavelet transform analysis", "Morlet wavelet transform" along with the terms "laser Doppler", "laserdoppler" and/or "flowmetry" or "fluxmetry". One hundred and eighteen studies have been found. After the scrutiny, 97 studies reporting data on humans have been selected. Fifty-three studies, 54.0% (95% CI 44.2-63.6) pooled rate, have been performed on 892 healthy subjects and 44, 45,9 % (95% CI 36.3-55.7%) pooled rate have been performed on 1679 patients. No significant difference has been found between the two groups (p 0,81). On average, the number of studies published each year was 4.8 (95% CI 3.4-6.2). The trend of studies production has increased significantly from 1998 to 2017, (p 0.0006). But only the studies on patients have shown a significant increase trend along the years (p 0.0003), than the studies on healthy subjects (p 0.09).In conclusion, this review highlights that despite being a promising and interesting methodology for the study of the microcirculatory function, the wavelet analysis has remained still neglected.

Wavelet transform analysis of skin perfusion during thermal stimulation.

This work elucidates the mechanisms of skin microcirculation response to local heating at 44°C in vasculopathic patients. Laser Doppler and tcpO2 were simultaneously acquired. Patients were selected on the basis of tcpO2: Group A <30 mmHg; Group B 30-50 mmHg; Group C >50 mmHg. The wavelet analysis of signal oscillations displays six frequency intervals. Each interval is assigned to a specific cardiovascular activity. The contributions of cardiac, myogenic and neurogenic activities were selectively detected. Thermal stimulation increased relative amplitude in all patients: heart activity by +103.26% in A, +162.84% in B, +454.54% in C; myogenic activity by +52.45% in A, +38.51% in B, +156.19% in C; neurogenic activity +43.36% in A, +74.15% in B, +242.42% in C. Thermal stimulation increased relative power in all patients: heart activity by +365.30% in A, +473.72% in B, +1393.77% in C; myogenic activity by +106.92% in A, +66.03% in B, +380.18% in C; neurogenic activity by +77.00% in A, +162.65% in B, +771.93% in C.This work demonstrates that the spectral analysis allows extracting from Laser Doppler signals more information than that can be gained by solely investigating perfusion values over time.

Wavelet analysis of the Laser Doppler signal to assess skin perfusion.

The hemodynamics of skin microcirculation can be clinically assessed by means of Laser Doppler Fluxmetry. Laser Doppler signals show periodic oscillations because of fluctuations of microvascular perfusion (flowmotion), which are sustained by contractions and relaxations of arteriolar walls rhythmically changing vessels diameter (vasomotion). The wavelet analysis applied to Laser Doppler signals displays six characteristic frequency intervals, from 0.005 to 2 Hz. Each interval is assigned to a specific structure of the cardiovascular system: heart, respiration, vascular myocites, sympathetic terminations, and endothelial cells (dependent and independent on nitric oxide). Therefore, mechanisms of skin perfusion can be investigated through wavelet analysis. In the present work, examples of methods and results of wavelet analysis applied to Laser Doppler signals are reported. Laser Doppler signals were acquired in two groups of patients to check possible changes in vascular activities, before and after occlusive reactive hyperaemia, and before and after revascularization.

Wavelet analysis of skin perfusion to assess the effects of FREMS therapy before and after occlusive reactive hyperemia.

Laser Doppler Fluxmetry is used to evaluate the hemodynamics of skin microcirculation. Laser Doppler signals contain oscillations due to fluctuations of microvascular perfusion. By performing spectral analysis, six frequency intervals from 0.005 to 2 Hz have been identified and assigned to distinct cardiovascular structures: heart, respiration, vascular myocites, sympathetic terminations and endothelial cells (dependent and independent on nitric oxide). Transcutaneous electrical pulses are currently applied to treat several diseases, i.e. neuropathies and chronic painful leg ulcers. Recently, FREMS (Frequency Rhythmic Electrical Modulation System) has been applied to vasculopathic patients, too. In this study Laser Doppler signals of skin microcirculation were measured in five patients with intermittent claudication, before and after the FREMS therapy. Changes in vascular activities were assessed by wavelet transform analysis. Preliminary results demonstrate that FREMS induces alterations in vascular activities.

L-propionyl-carnitine protects tissues from ischaemic injury in an 'in vivo' human ischaemia-reperfusion model.

OBJECTIVE: To assess the acute effects of L-propionyl-carnitine (LPC) on vaso-motion, tissue perfusion and tissue acidosis during an ischaemia-reperfusion test in patients with intermittent claudication. DESIGN: Open pharmacodynamic study. STUDY PARTICIPANTS: Sixteen male patients with intermittent claudication (mean absolute claudication distance 193.19 ± 51.51m). INTERVENTIONS: Intravenous infusion of LPC 600mg. MAIN OUTCOME MEASURES AND RESULTS: Laser-Doppler perfusion units and power spectrum, transcutaneous oxygen pressure (TcPO(2)) and transcutaneous carbon dioxide pressure (TcPCO(2)) were measured at baseline, during ischaemia (which was induced by means of an inflated pneumatic cuff wrapped around the calf) and during reperfusion, before and after LPC infusion. Perfusion units and TcPO(2) did not change significantly after LPC infusion compared with pretreatment values. Conversely, mean laser-Doppler power spectrum, which was 0.20 units at rest and 1.13 during reperfusion before treatment, increased significantly to 0.89 and 2.24, respectively, after LPC infusion (p = 0.01 and p = 0.00074, respectively, vs pretreatment values). LPC had no significant effects on resting TcPCO(2), but induced a significant decrease in TcPCO(2) measured at hypoxia point (96.9mm Hg before treatmentvs 90.2mm Hg after treatment; p = 0.001) and during reperfusion (115.9vs 103.5mm Hg, respectively; p = 0.0006). CONCLUSIONS: These results show that LPC protects tissues from ischaemic injury by improving arteriolar function and reducing acidosis, without affecting arterial inflow. This may explain the beneficial effects of LPC in patients with intermittent claudication and suggests a potential use of this drug in other stages of peripheral arterial disease and in patients undergoing surgery.