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European Journal of Vascular and... Jul 2019Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on...
Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.
Topics: Endovascular Procedures; Global Burden of Disease; Humans; International Cooperation; Ischemia; Limb Salvage; Lower Extremity; Peripheral Arterial Disease; Practice Guidelines as Topic; Prevalence; Quality of Life; Severity of Illness Index; Societies, Medical; Specialties, Surgical; Treatment Outcome
PubMed: 31182334
DOI: 10.1016/j.ejvs.2019.05.006 -
Critical Care (London, England) Jul 2019Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is an increasingly adopted life-saving mechanical circulatory support for a number of potentially reversible... (Review)
Review
Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is an increasingly adopted life-saving mechanical circulatory support for a number of potentially reversible or treatable cardiac diseases. It is also started as a bridge-to-transplantation/ventricular assist device in the case of unrecoverable cardiac or cardio-respiratory illness. In recent years, principally for non-post-cardiotomy shock, peripheral cannulation using the femoral vessels has been the approach of choice because it does not need the chest opening, can be quickly established, can be applied percutaneously, and is less likely to cause bleeding and infections than central cannulation. Peripheral ECMO, however, is characterized by a higher rate of vascular complications. The mechanisms of such adverse events are often multifactorial, including suboptimal arterial perfusion and hemodynamic instability due to the underlying disease, peripheral vascular disease, and placement of cannulas that nearly occlude the vessel. The effect of femoral artery damage and/or significant reduced limb perfusion can be devastating because limb ischemia can lead to compartment syndrome, requiring fasciotomy and, occasionally, even limb amputation, thereby negatively impacting hospital stay, long-term functional outcomes, and survival. Data on this topic are highly fragmentary, and there are no clear-cut recommendations. Accordingly, the strategies adopted to cope with this complication vary a great deal, ranging from preventive placement of antegrade distal perfusion cannulas to rescue interventions and vascular surgery after the complication has manifested.This review aims to provide a comprehensive overview of limb ischemia during femoral cannulation for VA-ECMO in adults, focusing on incidence, tools for early diagnosis, risk factors, and preventive and treating strategies.
Topics: Catheterization, Peripheral; Extracorporeal Membrane Oxygenation; Extremities; Humans; Incidence; Ischemia; Risk Factors
PubMed: 31362770
DOI: 10.1186/s13054-019-2541-3 -
British Journal of Hospital Medicine... May 2022Aneurysms are associated with significant complications if not diagnosed and managed appropriately. Popliteal arterial aneurysms are the most common peripheral aneurysm,...
Aneurysms are associated with significant complications if not diagnosed and managed appropriately. Popliteal arterial aneurysms are the most common peripheral aneurysm, and can cause pain, nerve compression, ischaemia and limb loss. Vascular surgery is an emerging specialty under the remit of general surgery, with the primary objectives of preventing death and limb loss. This article summarises the epidemiology, investigation and management of popliteal arterial aneurysms for vascular and non-vascular trainees.
Topics: Aneurysm; Humans; Ischemia; Popliteal Artery
PubMed: 35653317
DOI: 10.12968/hmed.2021.0572 -
Lancet (London, England) May 2023Chronic limb-threatening ischaemia is the severest manifestation of peripheral arterial disease and presents with ischaemic pain at rest or tissue loss (ulceration,... (Randomized Controlled Trial)
Randomized Controlled Trial
A vein bypass first versus a best endovascular treatment first revascularisation strategy for patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal revascularisation procedure to restore limb perfusion (BASIL-2):...
BACKGROUND
Chronic limb-threatening ischaemia is the severest manifestation of peripheral arterial disease and presents with ischaemic pain at rest or tissue loss (ulceration, gangrene, or both), or both. We compared the effectiveness of a vein bypass first with a best endovascular treatment first revascularisation strategy in terms of preventing major amputation and death in patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion.
METHODS
Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL)-2 was an open-label, pragmatic, multicentre, phase 3, randomised trial done at 41 vascular surgery units in the UK (n=39), Sweden (n=1), and Denmark (n=1). Eligible patients were those who presented to hospital-based vascular surgery units with chronic limb-threatening ischaemia due to atherosclerotic disease and who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. Participants were randomly assigned (1:1) to receive either vein bypass (vein bypass group) or best endovascular treatment (best endovascular treatment group) as their first revascularisation procedure through a secure online randomisation system. Participants were excluded if they had ischaemic pain or tissue loss considered not to be primarily due to atherosclerotic peripheral artery disease. Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug eluting stents. Participants were followed up for a minimum of 2 years. Data were collected locally at participating centres. In England, Wales, and Sweden, centralised databases were used to collect information on amputations and deaths. Data were analysed centrally at the Birmingham Clinical Trials Unit. The primary outcome was amputation-free survival defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population. Safety was assessed by monitoring serious adverse events up to 30-days after first revascularisation. The trial is registered with the ISRCTN registry, ISRCTN27728689.
FINDINGS
Between July 22, 2014, and Nov 30, 2020, 345 participants (65 [19%] women and 280 [81%] men; median age 72·5 years [62·7-79·3]) with chronic limb-threatening ischaemia were enrolled in the trial and randomly assigned: 172 (50%) to the vein bypass group and 173 (50%) to the best endovascular treatment group. Major amputation or death occurred in 108 (63%) of 172 patients in the vein bypass group and 92 (53%) of 173 patients in the best endovascular treatment group (adjusted hazard ratio [HR] 1·35 [95% CI 1·02-1·80]; p=0·037). 91 (53%) of 172 patients in the vein bypass group and 77 (45%) of 173 patients in the best endovascular treatment group died (adjusted HR 1·37 [95% CI 1·00-1·87]). In both groups the most common causes of morbidity and death, including that occurring within 30 days of their first revascularisation, were cardiovascular (61 deaths in the vein bypass group and 49 in the best endovascular treatment group) and respiratory events (25 deaths in the vein bypass group and 23 in the best endovascular treatment group; number of cardiovascular and respiratory deaths were not mutually exclusive).
INTERPRETATION
In the BASIL-2 trial, a best endovascular treatment first revascularisation strategy was associated with a better amputation-free survival, which was largely driven by fewer deaths in the best endovascular treatment group. These data suggest that more patients with chronic limb-threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion should be considered for a best endovascular treatment first revascularisation strategy.
FUNDING
UK National Institute of Health Research Health Technology Programme.
Topics: Male; Humans; Female; Aged; Chronic Limb-Threatening Ischemia; Ocimum basilicum; Ischemia; Angioplasty, Balloon, Coronary; Peripheral Arterial Disease; Risk Factors; Perfusion; Pain; Treatment Outcome
PubMed: 37116524
DOI: 10.1016/S0140-6736(23)00462-2 -
JACC. Cardiovascular Interventions Mar 2024Patients with chronic limb-threatening ischemia, the terminal stage of peripheral artery disease, are frequently afflicted by below-the-knee disease. Although all... (Review)
Review
Patients with chronic limb-threatening ischemia, the terminal stage of peripheral artery disease, are frequently afflicted by below-the-knee disease. Although all patients should receive guideline-directed medical therapy, restoration of inline flow is oftentimes necessary to avoid limb loss. Proper patient selection and proficiency in endovascular techniques for below-the-knee revascularization are intended to prevent major amputation and promote wound healing. This review, a consensus among an international panel of experienced operators, provides guidance on these challenges from an endovascular perspective and offers techniques to navigate this complex disease process.
Topics: Humans; Treatment Outcome; Risk Factors; Limb Salvage; Lower Extremity; Peripheral Arterial Disease; Endovascular Procedures; Ischemia; Retrospective Studies; Chronic Disease
PubMed: 38244007
DOI: 10.1016/j.jcin.2023.11.040 -
Arteriosclerosis, Thrombosis, and... Jun 2023Peripheral ischemia caused by peripheral artery disease is associated with systemic inflammation, which may aggravate underlying comorbidities such as atherosclerosis...
BACKGROUND
Peripheral ischemia caused by peripheral artery disease is associated with systemic inflammation, which may aggravate underlying comorbidities such as atherosclerosis and heart failure. However, the mechanisms of increased inflammation and inflammatory cell production in patients with peripheral artery disease remain poorly understood.
METHODS
We used peripheral blood collected from patients with peripheral artery disease and performed hind limb ischemia (HI) in mice fed a Western diet and C57BL/6J mice with a standard laboratory diet. Bulk and single-cell RNA sequencing analysis, whole-mount microscopy, and flow cytometry were performed to analyze hematopoietic stem and progenitor cell (HSPC) proliferation, differentiation, and relocation.
RESULTS
We observed augmented numbers of leukocytes in the blood of patients with peripheral artery disease and mice with HI. RNA sequencing and whole-mount imaging of the bone marrow revealed HSPC migration into the vascular niche from the osteoblastic niche and their exaggerated proliferation and differentiation. Single-cell RNA sequencing demonstrated alterations in the genes responsible for inflammation, myeloid cell mobilization, and HSPC differentiation after HI. Heightened inflammation in mice after HI aggravated atherosclerosis. Surprisingly, bone marrow HSPCs expressed higher amounts of the receptors for IL (interleukin)-1 and IL-3 after HI. Concomitantly, the promoters of and had augmented H3K4me3 and H3K27ac marks after HI. Genetic and pharmacological inhibition of these receptors resulted in suppressed HSPC proliferation, reduced leukocyte production, and ameliorated atherosclerosis.
CONCLUSIONS
Our findings demonstrate increased inflammation, HSPC abundance in the vascular niches of the bone marrow, and elevated IL-3Rb and IL-1R1 (IL-1 receptor 1) expression in HSPC following HI. Furthermore, the IL-3Rb and IL-1R1 signaling plays a pivotal role in HSPC proliferation, leukocyte abundance, and atherosclerosis aggravation after HI.
Topics: Animals; Mice; Mice, Inbred C57BL; Hematopoietic Stem Cells; Atherosclerosis; Inflammation; Ischemia; Peripheral Arterial Disease; Apolipoproteins E; Epigenesis, Genetic
PubMed: 36891902
DOI: 10.1161/ATVBAHA.123.318956 -
Clinical Therapeutics Nov 2023This narrative review summarizes recent research examining treatment targets for peripheral artery disease (PAD)-related limb ischemia. (Review)
Review
PURPOSE
This narrative review summarizes recent research examining treatment targets for peripheral artery disease (PAD)-related limb ischemia.
METHODS
Targeted searches of the PubMed and clinical trial registry databases were performed to identify recent findings from animal models of limb ischemia and clinical studies examining PAD progression and treatment. Ongoing clinical trials testing new treatments for PAD were also reviewed. Relevant full-text articles were retrieved and critically reviewed. Where indicated, data were tabulated and summarized in the text.
FINDINGS
Most people with PAD need treatment to improve their walking and function and limit leg pain. Currently, the available treatments of cilostazol, exercise therapy, and revascularization have several deficiencies, including limited access, poor uptake, limited efficacy, and risk of complications. Severe PAD threatens limb viability and is treated by endovascular or open surgical revascularization but is not always successful in achieving limb salvage. Research is ongoing to develop and test new therapies, including new exercise programs, drugs, stem cell treatments and RNA therapeutics, so that new and adjunctive PAD treatments can be offered. Results from multiple clinical trials are expected within the next 5 years.
IMPLICATIONS
It is envisaged that a range of new therapies for PAD will be available in the future.
Topics: Animals; Humans; Peripheral Arterial Disease; Ischemia; Limb Salvage; Walking; Treatment Outcome; Risk Factors
PubMed: 37770310
DOI: 10.1016/j.clinthera.2023.09.005 -
Seminars in Vascular Surgery Jun 2022Patients with chronic limb-threatening ischemia (CLTI) are medically complex and continue to experience high rates of amputation, despite improved diagnosis and... (Review)
Review
Patients with chronic limb-threatening ischemia (CLTI) are medically complex and continue to experience high rates of amputation, despite improved diagnosis and treatment. Limb salvage programs and multidisciplinary teams provide comprehensive patient care and have been associated with reduced amputation rates. Recent societal guidelines suggest the adoption of limb salvage programs to improve care of patients with CLTI. In this article, we describe the critical components of a limb salvage program and outline the following steps to aid in their construction: community and institution assessment, formation of a multidisciplinary team, provision of patient care, and monitoring outcomes and processes refinement.
Topics: Amputation, Surgical; Chronic Disease; Chronic Limb-Threatening Ischemia; Humans; Ischemia; Limb Salvage; Peripheral Arterial Disease; Retrospective Studies; Risk Factors; Treatment Outcome
PubMed: 35672113
DOI: 10.1053/j.semvascsurg.2022.04.011 -
Arteriosclerosis, Thrombosis, and... Mar 2020Peripheral artery disease, caused by chronic arterial occlusion of the lower extremities, affects over 200 million people worldwide. Peripheral artery disease can... (Review)
Review
Peripheral artery disease, caused by chronic arterial occlusion of the lower extremities, affects over 200 million people worldwide. Peripheral artery disease can progress into critical limb ischemia (CLI), its more severe manifestation, which is associated with higher risk of limb amputation and cardiovascular death. Aiming to improve tissue perfusion, therapeutic angiogenesis held promise to improve ischemic limbs using delivery of growth factors but has not successfully translated into benefits for patients. Moreover, accumulating studies suggest that impaired downstream signaling of these growth factors (or angiogenic resistance) may significantly contribute to CLI, particularly under harsh environments, such as diabetes mellitus. Noncoding RNAs are essential regulators of gene expression that control a range of pathophysiologies relevant to CLI, including angiogenesis/arteriogenesis, hypoxia, inflammation, stem/progenitor cells, and diabetes mellitus. In this review, we summarize the role of noncoding RNAs, including microRNAs and long noncoding RNAs, as functional mediators or biomarkers in the pathophysiology of CLI. A better understanding of these ncRNAs in CLI may provide opportunities for new targets in the prevention, diagnosis, and therapeutic management of this disabling disease state.
Topics: Animals; Critical Illness; Diabetes Mellitus; Gene Expression Regulation; Hemodynamics; Humans; Hypoxia; Inflammation; Ischemia; Neovascularization, Physiologic; Peripheral Arterial Disease; Prognosis; RNA, Untranslated; Regional Blood Flow; Risk Factors; Signal Transduction; Stem Cells
PubMed: 31893949
DOI: 10.1161/ATVBAHA.119.312860 -
Methodist DeBakey Cardiovascular Journal 2023Exercise has a profound effect on cardiovascular disease, particularly through vascular remodeling and regeneration. Peripheral artery disease (PAD) is one such... (Review)
Review
Exercise has a profound effect on cardiovascular disease, particularly through vascular remodeling and regeneration. Peripheral artery disease (PAD) is one such cardiovascular condition that benefits from regular exercise or rehabilitative physical therapy in terms of slowing the progression of disease and delaying amputations. Various rodent pre-clinical studies using models of PAD and exercise have shed light on molecular pathways of vascular regeneration. Here, I review key exercise-activated signaling pathways (nuclear receptors, kinases, and hypoxia inducible factors) in the skeletal muscle that drive paracrine regenerative angiogenesis. The rationale for highlighting the skeletal muscle is that it is the largest organ recruited during exercise. During exercise, skeletal muscle releases several myokines, including angiogenic factors and cytokines that drive tissue vascular regeneration via activation of endothelial cells, as well as by recruiting immune and endothelial progenitor cells. Some of these core exercise-activated pathways can be extrapolated to vascular regeneration in other organs. I also highlight future areas of exercise research (including metabolomics, single cell transcriptomics, and extracellular vesicle biology) to advance our understanding of how exercise induces vascular regeneration at the molecular level, and propose the idea of "exercise-mimicking" therapeutics for vascular recovery.
Topics: Humans; Endothelial Cells; Vascular Endothelial Growth Factor A; Muscle, Skeletal; Ischemia; Peripheral Arterial Disease; Exercise; Regeneration; Neovascularization, Physiologic
PubMed: 38028974
DOI: 10.14797/mdcvj.1304