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Arteriosclerosis, Thrombosis, and... Jun 2023Peripheral artery disease (PAD) is a vascular disorder caused by occlusive atherosclerosis, which commonly impairs blood flow to the lower extremities. The prevalence of... (Review)
Review
Peripheral artery disease (PAD) is a vascular disorder caused by occlusive atherosclerosis, which commonly impairs blood flow to the lower extremities. The prevalence of PAD is increasing globally with >200 million people affected. PAD remains a growing global health problem as the population continues to age and diabetes incidence grows. Many patients with PAD, most notably those with critical limb ischemia, fail attempts at surgical and percutaneous intervention to improve blood flow and are at risk of amputation. Gene therapy provides an opportunity to change the clinical course of PAD in these patients via strategies that increase vascular supply through angiogenesis and arteriogenesis improving muscle perfusion and function in ischemic legs. This article discusses gene therapy approaches in the context of PAD, both intermittent claudication and critical limb ischemia, and the promise of adeno-associated virus-based strategies delivering not just VEGFs (vascular endothelial growth factors) but a range of other mediators as potential new therapeutics. We also highlight challenges and failures in the clinical translation of gene therapy for PAD and how at least some of these obstacles may be overcome using adeno-associated virus.
Topics: Humans; Dependovirus; Chronic Limb-Threatening Ischemia; Peripheral Arterial Disease; Intermittent Claudication; Lower Extremity; Ischemia
PubMed: 37128915
DOI: 10.1161/ATVBAHA.122.318902 -
Journal of Vascular Surgery Feb 2021Acute limb ischemia (ALI) and cannulation site bleeding are frequent complications of venoarterial (VA) extracorporeal membrane oxygenation (ECMO) and are associated...
OBJECTIVE
Acute limb ischemia (ALI) and cannulation site bleeding are frequent complications of venoarterial (VA) extracorporeal membrane oxygenation (ECMO) and are associated with worse outcomes. The goals of this study were to assess our rates of ECMO-related ALI and bleeding and to evaluate the efficacy of strategies to prevent them, such as distal perfusion cannula (DPC) and ultrasound-guided cannulation.
METHODS
This is a single-center retrospective cohort study of adult patients placed on peripheral VA-ECMO at a tertiary medical center between 2014 and 2018. ALI was defined as new ischemia of the extremity ipsilateral to arterial cannulation. Significant cannulation site bleeding was defined as excessive bleeding requiring intervention (eg, transfusion or reoperation). Univariate analyses were used to identify factors associated with ALI, bleeding, and in-hospital mortality.
RESULTS
During the study period, 105 patients were placed on peripheral VA-ECMO (61.3% female; mean age, 54.9 ± 14.8 years). Nearly half (46.6%) had ECMO implantation in an extracorporeal cardiopulmonary resuscitation setting and 37 (44.0%) had a DPC. Average duration of support was 5.6 ± 5.0 days. Overall in-hospital mortality and death on ECMO support were 65.1% and 50%, respectively. ALI occurred in 21 (20%) and cannulation-related bleeding occurred in 24 (22.9%) patients who were treated with a total of 27 procedures, including thromboembolectomy (22.2%), vascular repair (18.5%), and fasciotomy (25.9%). On univariate analysis, cannulation in the operating room (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.08-0.77; P = .02) was associated with decreased risk of ALI, whereas cannulation in the operating room (OR, 2.65; 95% CI, 1.09-6.45; P = .03) and cutdown approach (OR, 4.96; 95% CI, 2.32-10.61; P < .0001) were associated with increased risk of bleeding. Ultrasound-guided placement was associated with decreased risk of bleeding (OR, 0.81; 95% CI, 0.04-0.84; P = .03). DPC was not associated with either ALI (P = .47) or bleeding (P = .06). ALI (OR, 2.68; 95% CI 1.03-6.98; P = .04), age (OR, 1.94; 95% CI, 1.03-3.69; P = .04), and worse baseline heart failure (OR, 2.01; 95% CI, 1.02-3.97; P = .04) were associated with greater risk of in-hospital mortality. Ultrasound-guided cannulation (OR, 0.41; 95% CI, 0.20-0.87; P = .02) was associated with decreased risk of in-hospital mortality.
CONCLUSIONS
ALI and significant bleeding are common occurrences after peripheral VA-ECMO cannulation. Whereas DPC placement did not significantly decrease risk of ALI, ultrasound-guided cannulation decreased the risk of bleeding. Cannulation in the operating room is associated with decreased risk of ALI at the expense of increased risk of bleeding. ALI, older age (≥65 years), and worse heart failure increased risk of in-hospital mortality.
Topics: Adult; Aged; Catheterization; Extracorporeal Membrane Oxygenation; Extremities; Female; Hemorrhage; Hospital Mortality; Humans; Ischemia; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Ultrasonography, Interventional
PubMed: 32623105
DOI: 10.1016/j.jvs.2020.05.071 -
Current Gene Therapy 2022Peripheral artery diseases remain a serious public health problem. Although there are many traditional methods for their treatment using conservative therapeutic... (Review)
Review
Peripheral artery diseases remain a serious public health problem. Although there are many traditional methods for their treatment using conservative therapeutic techniques and surgery, gene therapy is an alternative and potentially more effective treatment option especially for "no-option" patients. This review treats the results of many years of research and application of gene therapy as an example of treatment of patients with critical limb ischemia. Data on successful and unsuccessful attempts to use this technology for treating this disease are presented. Trends in changing the paradigm of approaches to therapeutic angiogenesis are noted: from viral vectors to non-viral vectors, from gene transfer to the whole organism to targeted transfer to cells and tissues, from single-gene use to combination of genes; from DNA therapy to RNA therapy, from in vivo therapy to ex vivo therapy.
Topics: Chronic Limb-Threatening Ischemia; Genetic Therapy; Genetic Vectors; Humans; Ischemia; Neovascularization, Pathologic; Neovascularization, Physiologic
PubMed: 34254916
DOI: 10.2174/1566523221666210712185742 -
Circulation. Cardiovascular... Jan 2024
Topics: Humans; Chronic Limb-Threatening Ischemia; Treatment Outcome; Peripheral Arterial Disease; Chronic Disease; Ischemia; Limb Salvage; Retrospective Studies; Risk Factors; Endovascular Procedures
PubMed: 38152882
DOI: 10.1161/CIRCINTERVENTIONS.123.013693 -
The Journal of Surgical Research Aug 2023Mitochondrial dysfunction is implicated in the metabolic myopathy accompanying peripheral artery disease (PAD) and critical limb ischemia (CLI). Type-2 diabetes mellitus...
INTRODUCTION
Mitochondrial dysfunction is implicated in the metabolic myopathy accompanying peripheral artery disease (PAD) and critical limb ischemia (CLI). Type-2 diabetes mellitus (T2DM) is a major risk factor for PAD development and progression to CLI and may also independently be related to mitochondrial dysfunction. We set out to determine the effect of T2DM in the relationship between CLI and muscle mitochondrial respiratory capacity and coupling control.
METHODS
We studied CLI patients undergoing revascularization procedures or amputation, and non-CLI patients with or without T2DM of similar age. Mitochondrial respiratory capacity and function were determined in lower limb permeabilized myofibers by high-resolution respirometry.
RESULTS
Fourteen CLI patients (65 ± 10y) were stratified into CLI patients with (n = 8) or without (n = 6) T2DM and were compared to non-CLI patients with (n = 18; 69 ± 5y) or without (n = 19; 71 ± 6y) T2DM. Presence of CLI but not T2DM had a marked impact on all mitochondrial respiratory states in skeletal muscle, adjusted for the effects of sex. Leak respiration (State 2, P < 0.025 and State 4, P < 0.01), phosphorylating respiration (P < 0.001), and maximal respiration in the uncoupled state (P < 0.001), were all suppressed in CLI patients, independent of T2DM. T2DM had no significant effect on mitochondrial respiratory capacity and function in adults without CLI.
CONCLUSIONS
Skeletal muscle mitochondrial respiratory capacity was blunted by ∼35% in patients with CLI. T2DM was not associated with muscle oxidative capacity and did not moderate the relationship between muscle mitochondrial respiratory capacity and CLI.
Topics: Adult; Humans; Chronic Limb-Threatening Ischemia; Muscle, Skeletal; Peripheral Arterial Disease; Risk Factors; Energy Metabolism; Ischemia; Treatment Outcome; Limb Salvage; Diabetes Mellitus
PubMed: 36963297
DOI: 10.1016/j.jss.2023.02.015 -
International Journal of Molecular... Nov 2023Critical limb ischemia incidence and prevalence have increased over the years. However, there are no successful treatments to improve quality of life and to reduce the... (Review)
Review
Critical limb ischemia incidence and prevalence have increased over the years. However, there are no successful treatments to improve quality of life and to reduce the risk of cardiovascular and limb events in these patients. Advanced regenerative therapies have focused their interest on the generation of new blood vessels to repair tissue damage through the use of stem cells. One of the most promising sources of stem cells with high potential in cell-based therapy is adipose-derived stem cells (ASCs). ASCs are adult mesenchymal stem cells that are relatively abundant and ubiquitous and are characterized by a multilineage capacity and low immunogenicity. The proangiogenic benefits of ASCs may be ascribed to: (a) paracrine secretion of proangiogenic molecules that may stimulate angiogenesis; (b) secretion of microvesicles/exosomes that are also considered as a novel therapeutic prospect for treating ischemic diseases; and (c) their differentiation capability toward endothelial cells (ECs). Although we know the proangiogenic effects of ASCs, the therapeutic efficacy of ASCs after transplantation in peripheral artery diseases patients is still relatively low. In this review, we evidence the potential therapeutic use of ASCs in ischemic regenerative medicine. We also highlight the main challenges in the differentiation of these cells into functional ECs. However, significant efforts are still needed to ascertain relevant transcription factors, intracellular signaling and interlinking pathways in endothelial differentiation.
Topics: Adult; Humans; Adipose Tissue; Endothelial Cells; Quality of Life; Ischemia; Stem Cells; Peripheral Arterial Disease; Cell Differentiation; Neovascularization, Physiologic
PubMed: 38069074
DOI: 10.3390/ijms242316752 -
Optometry and Vision Science : Official... Apr 2021Although von Willebrand disease is the most common inherited bleeding disorder, there are only a few published reports of ocular complications. To our knowledge, this is...
SIGNIFICANCE
Although von Willebrand disease is the most common inherited bleeding disorder, there are only a few published reports of ocular complications. To our knowledge, this is the first case of peripheral retinal ischemia and retinal neovascularization in a patient with von Willebrand disease.
PURPOSE
This study aimed to demonstrate the value of multispecialty care when exploring a diagnosis for bilateral retinopathy.
CASE REPORT
A 55-year-old African American woman presented with peripheral retinal hemorrhages on routine examination. She was asymptomatic and did not have any personal or family history of bleeding disorders. Blood work was ordered, and she was referred to a retinal specialist who found peripheral telangiectasia, retinal ischemia, and leakage on fluorescein angiography, consistent with retinal neovascularization. Laser photocoagulation was performed while numerous specialists were consulted to determine the cause for her retinopathy. Laboratory testing confirmed low-grade type 1 von Willebrand disease. She was monitored without systemic treatment. She remained stable and asymptomatic, but her retinal neovascularization did not regress fully, so laser treatment was repeated.
CONCLUSIONS
This case described a new finding of peripheral retinal ischemia and retinal neovascularization in von Willebrand disease. It was discovered in an asymptomatic patient who did not have a history of bleeding but presented with bilateral retinal hemorrhages. Diagnosis was challenging because of the high degree of variation in this bleeding disorder, requiring extensive testing and careful consideration of the individual's clinical profile. Most people with von Willebrand disease do not know they have the disease because symptoms are mild or absent, so most cases are unreported. The von Willebrand factor is poorly recognized in ocular disease, but given its role in angiogenesis, it may be a valuable target to consider in future research.
Topics: Female; Fluorescein Angiography; Humans; Ischemia; Middle Aged; Retinal Neovascularization; Retinal Vessels; Visual Acuity; von Willebrand Diseases; von Willebrand Factor
PubMed: 33828041
DOI: 10.1097/OPX.0000000000001670 -
The Cochrane Database of Systematic... Nov 2021Acute limb ischaemia usually is caused by a blood clot blocking an artery or a bypass graft. Severe acute ischaemia will lead to irreversible damage to muscles and... (Review)
Review
BACKGROUND
Acute limb ischaemia usually is caused by a blood clot blocking an artery or a bypass graft. Severe acute ischaemia will lead to irreversible damage to muscles and nerves if blood flow is not restored in a few hours. Once irreversible damage occurs, amputation will be necessary and the condition can be life-threatening. Infusion of clot-busting drugs (thrombolysis) is a useful tool in the management of acute limb ischaemia. Fibrinolytic drugs are used to disperse blood clots (thrombi) to clear arterial occlusion and restore blood flow. Thrombolysis is less invasive than surgery. A variety of techniques are used to deliver fibrinolytic agents. This is an update of a review first published in 2004.
OBJECTIVES
To compare the effects of infusion techniques during peripheral arterial thrombolysis for treatment of patients with acute limb ischaemia.
SEARCH METHODS
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries to 20 October 2020. We undertook reference checking to identify additional studies.
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) comparing infusion techniques for fibrinolytic agents in the treatment of acute limb ischaemia.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures as recommended by Cochrane. We assessed the risk of bias in included trials using the Cochrane 'Risk of bias' tool. We evaluated certainty of evidence using GRADE. For dichotomous outcomes, we calculated the odds ratio (OR) with the corresponding 95% confidence interval (CI). We were not able to carry out meta-analyses due to clinical heterogeneity, so we have reported the results and performed the comparisons narratively. The main outcomes of interest were amputation-free survival or limb salvage, amputation, mortality, vessel patency, duration of thrombolysis, and complications such as cerebrovascular accident and major and minor bleeding.
MAIN RESULTS
Nine studies with a total of 671 participants are included in this update. Trials covered a variety of infusion techniques, dosage regimens, and adjunctive agents. We grouped trials according to types of techniques assessed (e.g. intravenous and intra-arterial delivery of the agent, 'high-' and 'low-dose' regimens of the agent, continuous infusion and 'forced infusion' of the agent, use of adjunctive antiplatelet agents). We assessed the certainty of evidence as very low to low due to the limited power of individual studies to deliver clinically relevant results, small and heterogeneous study populations, use of different inclusion criteria by each study in terms of severity and duration of ischaemia, considerably different outcome measures between trials, and use of different fibrinolytic agents. This heterogeneity prevented pooling of data in meta-analyses. No regimen has been shown to confer benefit in terms of amputation-free survival (at 30 days), amputation, or death. For vessel patency, complete success was more likely with intra-arterial (IA) than with intravenous (IV) infusion (odds ratio (OR) 13.22, 95% confidence interval (CI) 2.79 to 62.67; 1 study, 40 participants; low-certainty evidence); radiological failure may be more likely with IV infusion (OR 0.02, 95% CI 0.00 to 0.38; 1 study, 40 participants; low-certainty evidence). Due to the small numbers involved in each arm and design differences between arms, it is not possible to conclude whether any technique offered any advantage over another. None of the treatment strategies clearly affected complications such as cerebrovascular accident or major bleeding requiring surgery or blood transfusion. Minor bleeding complications were more frequent in systemic (intravenous) therapy compared to intra-arterial infusion (OR 0.03, 95% CI 0.00 to 0.56; 1 study, 40 participants), and in high-dose compared to low-dose therapy (OR 0.11, 95% CI 0.01 to 0.96; 1 study, 63 participants). Limited evidence from individual trials appears to indicate that high-dose and forced-infusion regimens reduce the duration of thrombolysis. In one trial, the median duration of infusion was 4 hours (range 0.25 to 46) for the high-dose group and 20 hours (range 2 to 46) for the low-dose group. In a second trial, treatment using pulse spray was continued for a median of 120 minutes (range 40 to 310) compared with low-dose infusion for a median of 25 hours (range 2 to 60). In a third trial, the median duration of therapy was reduced with pulse spray at 195 minutes (range 90 to 1260 minutes) compared to continuous infusion at 1390 minutes (range 300 to 2400 minutes). However, none of the studies individually showed improvement in limb salvage at 30 days nor benefit for the amputation rate related to the technique of drug delivery. Similarly, no studies reported a clear difference in occurrence of cerebrovascular accident or major bleeding. Although 'high-dose' and 'forced-infusion' techniques achieved vessel patency in less time than 'low-dose' infusion, more minor bleeding complications may be associated (OR 0.11, 95% CI 0.01 to 0.96; 1 study, 72 participants; and OR 0.48, 95% CI 0.17 to 1.32; 1 study, 121 participants, respectively). Use of adjunctive platelet glycoprotein IIb/IIIa antagonists did not improve outcomes, and results were limited by inclusion of participants with non-limb-threatening ischaemia.
AUTHORS' CONCLUSIONS
There is insufficient evidence to show that any thrombolytic regimen provides a benefit over any other in terms of amputation-free survival, amputation, or 30-day mortality. The rate of CVA or major bleeding requiring surgery or blood transfusion did not clearly differ between regimens but may occur more frequently in high dose and IV regimens. This evidence was limited and of very low certainty. Minor bleeding may be more common with high-dose and IV regimens. In this context, thrombolysis may be an acceptable therapy for patients with marginally threatened limbs (Rutherford grade IIa) compared with surgery. Caution is advised for patients who do not have limb-threatening ischaemia (Rutherford grade I) because of risks of major haemorrhage, cerebrovascular accident, and death from thrombolysis.
Topics: Amputation, Surgical; Arteries; Fibrinolytic Agents; Humans; Ischemia; Thrombolytic Therapy
PubMed: 34786692
DOI: 10.1002/14651858.CD000985.pub3 -
Cardiovascular Journal of AfricaCritical limb ischaemia (CLI) is the most severe state of peripheral arterial disease and is one of the major causes of lower-limb amputations. One of the treatment...
OBJECTIVE
Critical limb ischaemia (CLI) is the most severe state of peripheral arterial disease and is one of the major causes of lower-limb amputations. One of the treatment choices is prosthetic vascular grafts. Despite treatment, CLI may lead to amputation owing to infection or progressive ischaemia. The aim of this study was to show that multidisciplinary planning and surgery for CLI patients with prosthetic grafts decreased the duration of hospital stay, costs, risk of infection and ascending conversion of the amputation level.
METHODS
Forty-two above-knee amputation patients with grafts were retrospectively evaluated. Group A patients ( = 24) had partial excision and group B patients ( = 18) total excision with or without saphenous patch-plasty, according to the patency of the deep femoral artery. Growth in wound culture, antibiotic therapy duration, conversion to hip disarticulation and hospitalisation periods were compared.
RESULTS
Differences in growth of wound culture ( = 0.007), antibiotic duration ( = 0.003), hip disarticulation ( = 0.029) and duration of hospital stay ( = 0.0001) between the two groups were found to be statistically significant ( < 0.05).
CONCLUSIONS
Management of CLI patients is a complex process, and a multidisciplinary approach is key to avoiding undesirable outcomes. Meticulous planning, including excision of the total graft, while ensuring the vascular supply, is essential.
Topics: Humans; Retrospective Studies; Vascular Patency; Blood Vessel Prosthesis; Peripheral Arterial Disease; Ischemia; Amputation, Surgical; Treatment Outcome
PubMed: 35211716
DOI: 10.5830/CVJA-2022-012 -
British Journal of Nursing (Mark Allen... Jul 2021This article will discuss chronic limb ischaemia as the result of peripheral artery disease (PAD) using a case study. The patient's concurrent diagnosis of metastases... (Review)
Review
This article will discuss chronic limb ischaemia as the result of peripheral artery disease (PAD) using a case study. The patient's concurrent diagnosis of metastases meant clinical decision making was complex and treatment options were limited. PAD is the third most common clinical presentation of atherosclerosis after coronary artery disease and stroke. Although advances in radiological technology and biochemical screening offer the potential for earlier intervention and improved survival rates for patients with PAD, a review of the evidence suggests that commitment to more conservative approaches, such as exercise therapy and health promotion, could have more sustainable, longer-term benefits for patients with chronic limb ischaemia. The therapeutic nature of the nurse-patient relationship makes nurses ideally placed for encouraging lifestyle changes and signposting to support services. Active participation from the patient is imperative for any potential modifications, which should be individualised as part of a holistic care plan, to ensure patient engagement and compliance. Therefore emphasis should remain on the management and prevention of modifiable risk factors, for which the nurse's role is an integral part to ensure success.
Topics: Chronic Disease; Humans; Ischemia; Peripheral Arterial Disease
PubMed: 34288743
DOI: 10.12968/bjon.2021.30.14.846