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Journal of Vascular Surgery May 2022Chronic limb-threatening ischemia (CLTI) causes significant morbidity with profound negative effects on health-related quality of life. As the prevalence of peripheral... (Review)
Review
Chronic limb-threatening ischemia (CLTI) causes significant morbidity with profound negative effects on health-related quality of life. As the prevalence of peripheral artery disease and diabetes continue to rise in our aging population, the public health impact of CLTI has escalated. Patient-reported outcome measures (PROMs) have become common and important measures for clinical evaluation in both clinical care and research. PROMs are important for the measurement of clinical effectiveness and cost effectiveness and for shared decision-making on treatment options. However, the PROMs used to describe the experience of patients with CLTI are heterogeneous, incomplete, and lack specific applicability to the underlying disease processes and diverse populations. For example, certain PROMs exist for patients with extremity wounds, and other PROMs exist for patients with pain, and still others exist for patients with vascular disease. Despite this multiplicity of tools, no single PROM encompasses all of the components necessary to describe the experiences of patients with CLTI. This significant unmet need is evident from both published reports and contemporary large-scale clinical trials in the field. In this systematic review, we review the current use of PROMs for patients with CLTI in clinical practice and in research trials and highlight the gaps that need to be addressed to develop a unifying PROM instrument for CLTI.
Topics: Aged; Amputation, Surgical; Chronic Disease; Chronic Limb-Threatening Ischemia; Humans; Ischemia; Limb Salvage; Patient Reported Outcome Measures; Peripheral Arterial Disease; Quality of Life; Retrospective Studies; Risk Factors; Treatment Outcome
PubMed: 35085747
DOI: 10.1016/j.jvs.2021.11.057 -
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 -
Cardiovascular Research Mar 2019Peripheral arterial disease (PAD) is the leading cause of lower limb amputation and estimated to affect over 202 million people worldwide. PAD is caused by... (Review)
Review
Peripheral arterial disease (PAD) is the leading cause of lower limb amputation and estimated to affect over 202 million people worldwide. PAD is caused by atherosclerotic lesions that occlude large arteries in the lower limbs, leading to insufficient blood perfusion of distal tissues. Given the severity of this clinical problem, there has been long-standing interest in both understanding how chronic arterial occlusions affect muscle tissue and vasculature and identifying therapeutic approaches capable of restoring tissue composition and vascular function to a healthy state. To date, the most widely utilized animal model for performing such studies has been the ischaemic mouse hindlimb. Despite not being a model of PAD per se, the ischaemic hindlimb model does recapitulate several key aspects of PAD. Further, it has served as a valuable platform upon which we have built much of our understanding of how chronic arterial occlusions affect muscle tissue composition, muscle regeneration and angiogenesis, and collateral arteriogenesis. Recently, there has been a global surge in research aimed at understanding how gene expression is regulated by epigenetic factors (i.e. non-coding RNAs, histone post-translational modifications, and DNA methylation). Thus, perhaps not unexpectedly, many recent studies have identified essential roles for epigenetic factors in regulating key responses to chronic arterial occlusion(s). In this review, we summarize the mechanisms of action of these epigenetic regulators and highlight several recent studies investigating the role of said regulators in the context of hindlimb ischaemia. In addition, we focus on how these recent advances in our understanding of the role of epigenetics in regulating responses to chronic arterial occlusion(s) can inform future therapeutic applications to promote revascularization and perfusion recovery in the setting of PAD.
Topics: Animals; Chronic Disease; Collateral Circulation; Disease Models, Animal; Epigenesis, Genetic; Hindlimb; Humans; Ischemia; Mice; Muscle, Skeletal; Neovascularization, Physiologic; Peripheral Arterial Disease; Rats; Regeneration; Regional Blood Flow
PubMed: 30629133
DOI: 10.1093/cvr/cvz001 -
Diabetes/metabolism Research and Reviews Mar 2024Diabetes is a key risk factor for ischaemic foot disease, which causes pain, tissue loss, hospital admission, and major amputation. Currently, treatment focuses on... (Review)
Review
Diabetes is a key risk factor for ischaemic foot disease, which causes pain, tissue loss, hospital admission, and major amputation. Currently, treatment focuses on revascularisation, but many patients are unsuitable for surgery and revascularisation is frequently unsuccessful. The authors describe recent research in animal models and clinical trials investigating novel medical targets for ischaemia, including theories about impaired wound healing, animal models for limb ischaemia and recent randomised controlled trials testing novel medical therapies. Novel targets identified in animal models included stimulating mobilisation of CD34+ progenitor cells through upregulating oncostatin M or microRNA-181, downregulating tumour necrosis factor superfamily member 14, or activating the Wingless pathway. Within the ischaemic limb vasculature, upregulation of apolipoprotein L domain containing 1, microRNA-130b or long noncoding RNA that enhances endothelial nitric oxide synthase expression promoted limb blood supply recovery, angiogenesis, and arteriogenesis. Similarly, administration of soluble guanylate cyclase stimulators riociguat or praliciguat or 3-ketoacyl-CoA thiolase inhibitor trimetazidine promoted blood flow recovery. Translating pre-clinical findings to patients has been challenging, mainly due to limitations in clinically translatable animal models of human disease. Promising results have been reported for administering plasmids encoding hepatocyte growth factor or intra-arterial injection of bone marrow derived cells in small clinical trials. It remains to be seen whether these high resource therapies can be developed to be widely applicable. In conclusion, an ever-expanding list of potential targets for medical revascularisation is being identified. It is hoped that through ongoing research and further larger clinical trials, these will translate into new broadly applicable therapies to improve outcomes.
Topics: Animals; Humans; Ischemia; Risk Factors; Foot Diseases; MicroRNAs
PubMed: 37563926
DOI: 10.1002/dmrr.3703 -
Surgery Mar 2023Mechanical circulatory support effectively treats adult cardiogenic shock. Whereas cardiogenic shock confers high mortality, acute limb ischemia is a known complication...
Peripherally inserted concomitant surgical right and left ventricular support, the Propella, is associated with low rates of limb ischemia, with mortality comparable with peripheral venoarterial extracorporeal membrane oxygenation.
BACKGROUND
Mechanical circulatory support effectively treats adult cardiogenic shock. Whereas cardiogenic shock confers high mortality, acute limb ischemia is a known complication of mechanical circulatory support that confers significant morbidity. We compared our novel approach to peripheral mechanical circulatory support with a conventional femoral approach, with a focus on the incidence of acute limb ischemia.
METHODS
This was a retrospective cohort study of patients treated with mechanical circulatory support between January 1, 2015 and December 5, 2021 at our institution. Patients receiving any femoral peripheral venoarterial extracorporeal membrane oxygenation were compared with those receiving minimally invasive, peripherally inserted, concomitant right and left ventricular assist devices. These included the Impella 5.0 (Abiomed, Danvers, MA) left ventricular assist device and the ProtekDuo (LivaNova, London, UK) right ventricular assist device used concomitantly (Propella) approach. The primary outcome was incidence of acute limb ischemia. The baseline patient characteristics, hemodynamic data, and post-mechanical circulatory support outcomes were collected. Fisher exact test and Wilcoxon rank sum test was used for the categorical and continuous variables, respectively. Kaplan-Meier curves and log-rank test were used to estimate overall survival probabilities and survival experience, respectively.
RESULTS
Fifty patients were treated with mechanical circulatory support at our institution for cardiogenic shock, with 13 patients supported with the novel Propella strategy and 37 with peripheral venoarterial extracorporeal membrane oxygenation. The baseline characteristics, including patient organ function and medical comorbidities, were similar among the groups. Nine patients suffered mortality in ≤48 hours of mechanical circulatory support initiation and were excluded. Twenty patients (69%) suffered acute limb ischemia in the peripheral venoarterial extracorporeal membrane oxygenation group; 0 patients receiving Propella suffered acute limb ischemia (P < .001). The percentages of patients surviving to discharge in peripheral venoarterial extracorporeal membrane oxygenation and Propella groups were 24% and 69%, respectively (P = .007).
CONCLUSION
Patients treated with the Propella experienced a lower incidence of acute limb ischemia compared with patients treated with peripheral venoarterial extracorporeal membrane oxygenation.
Topics: Adult; Humans; Shock, Cardiogenic; Retrospective Studies; Extracorporeal Membrane Oxygenation; Ischemia; Heart-Assist Devices
PubMed: 36435648
DOI: 10.1016/j.surg.2022.10.007 -
Journal of the American Heart... Nov 2021Background Ankle-brachial index (ABI) is used to identify lower-extremity peripheral artery disease (PAD). However, its association with severe ischemic leg outcomes...
Background Ankle-brachial index (ABI) is used to identify lower-extremity peripheral artery disease (PAD). However, its association with severe ischemic leg outcomes (eg, amputation) has not been investigated in the general population. Methods and Results Among 13 735 ARIC (Atherosclerosis Risk in Communities) study participants without clinical manifestations of PAD (mean age, 54 [SD, 5.8] years; 44.4% men; and 73.6% White) at baseline (1987-1989), we quantified the prospective association between ABI and subsequent severe ischemic leg outcomes, critical limb ischemia (PAD with rest pain or tissue loss) and ischemic leg amputation (PAD requiring amputation) according to discharge diagnosis. Over a median follow-up of ≈28 years, there were 221 and 129 events of critical limb ischemia and ischemic leg amputation, respectively. After adjusting for demographics, ABI ≤0.90 versus 1.11 to 1.20 had a ≈4-fold higher risk of critical limb ischemia and ischemic leg amputation (hazard ratios, 3.85 [95% CI, 2.09-7.11] and 4.39 [95% CI, 2.08-9.27]). The magnitude of the association was modestly attenuated after multivariable adjustment (hazard ratios, 2.44 [95% CI, 1.29-4.61] and 2.72 [95% CI, 1.25-5.91], respectively). ABI 0.91 to 1.00 and 1.01 to 1.10 were also associated with these severe leg outcomes, with hazard ratios ranging from 1.7 to 2.0 after accounting for potential clinical and demographic confounders. The associations were largely consistent across various subgroups. Conclusions In a middle-aged community-based cohort, lower ABI was independently and robustly associated with increased risk of severe ischemic leg outcomes. Our results further support ABI ≤0.90 as a threshold diagnosing PAD and also suggest the importance of recognizing the prognostic value of ABI 0.91 to 1.10 for limb prognosis.
Topics: Ankle Brachial Index; Chronic Limb-Threatening Ischemia; Female; Humans; Ischemia; Leg; Male; Middle Aged; Peripheral Arterial Disease; Risk Factors
PubMed: 34726067
DOI: 10.1161/JAHA.121.021801 -
Vascular Medicine (London, England) Apr 2021
Topics: Amputation, Surgical; Chronic Limb-Threatening Ischemia; Critical Illness; Humans; Ischemia; Limb Salvage; Peripheral Arterial Disease; Risk Factors; Treatment Outcome
PubMed: 33825576
DOI: 10.1177/1358863X211000425 -
Vascular Health and Risk Management 2019Peripheral arterial disease is a chronic vascular disease characterized by impaired circulation to the lower extremities. Its most severe stage, known as critical limb... (Review)
Review
Peripheral arterial disease is a chronic vascular disease characterized by impaired circulation to the lower extremities. Its most severe stage, known as critical limb ischemia (CLI), puts patients at an increased risk of cardiovascular events, amputation, and death. The objective of this literature review is to describe the burden of disease across a comprehensive set of domains-epidemiologic, clinical, humanistic, and economic-focusing on key studies published in the last decade. CLI prevalence in the United States is estimated to be approximately 2 million and is likely to rise in the coming years given trends in important risk factors such as age, diabetes, and smoking. Hospitalization for CLI patients is common and up to 60% are readmitted within 6 months. Amputation rates are unacceptably high with a disproportionate risk for certain demographic and socioeconomic groups. In addition to limb loss, CLI patients also have reduced life expectancy with mortality typically exceeding 50% by 5 years. Given the poor clinical prognosis, it is unsurprising that the quality of life burden associated with CLI is significant. Studies assessing quality of life in CLI patients have used a variety of generic and disease-specific measures and all document a substantial impact of the disease on the patient's physical, social, and emotional health status compared to population norms. Finally, the poor clinical outcomes and increased medical resource use lead to a considerable economic burden for national health care systems. However, published cost studies are not comprehensive and, therefore, likely underestimate the true economic impact of CLI. Our summary documents a sobering assessment of CLI burden-a poor clinical prognosis translating into diminished quality of life and high costs for millions of patients. Continued prevention efforts and improved treatment strategies are the key to ameliorating the substantial morbidity and mortality associated with this disease.
Topics: Amputation, Surgical; Cost of Illness; Critical Illness; Health Care Costs; Humans; Incidence; Ischemia; Limb Salvage; Lower Extremity; Peripheral Arterial Disease; Prevalence; Quality of Life; Risk Factors; Treatment Outcome; United States
PubMed: 31308682
DOI: 10.2147/VHRM.S209241 -
The Journal of Cardiovascular Surgery Oct 2015Critical limb ischemia (CLI) encompasses the most extreme end of the peripheral artery disease (PAD) spectrum leading to significant morbidity and mortality. CLI is... (Review)
Review
Critical limb ischemia (CLI) encompasses the most extreme end of the peripheral artery disease (PAD) spectrum leading to significant morbidity and mortality. CLI is defined as greater than 2 weeks of extremity rest pain, ulcers or extremity gangrene, secondary to objectively proven peripheral artery disease. Corresponding to Fontaine Stages III/IV and Rutherford category IV through VI, CLI is a complex disease comprising of both macrovascular and microvascular systems with inconsistent historical data on optimal treatment. CLI is distinct from intermittent claudication with different goals of treatment, however in both groups risk factor modification is of the utmost importance involving tobacco cessation, and treatment of underlying conditions like diabetes mellitus, hyperlipidemia and hypertension. In CLI, medical therapy involves wound care and also consists of antiplatelet therapy, anti-inflammatory therapy including statin use or ACE inhibitors. Surgical therapies include distal bypass surgery, thromboendartectomy and amputation. Endovascular techniques include percutaneous transluminal angioplasty, bare metal stents, atherectomy, drug-coated balloon and drug-eluting stents. CLI is considered the end-stage of PAD, requiring a thoughtful and multidisciplinary approach, risk-benefit analysis and treatment of comorbid conditions. Conservative and surgical treatments, along with endovascular techniques, have allowed excellent opportunities for treating complicated patients for wound healing and limb salvage.
Topics: Amputation, Surgical; Cardiovascular Agents; Critical Illness; Endovascular Procedures; Humans; Ischemia; Limb Salvage; Peripheral Arterial Disease; Risk Factors; Risk Reduction Behavior; Treatment Outcome; Vascular Surgical Procedures; Wound Healing
PubMed: 25868972
DOI: No ID Found -
Vascular Feb 2022Revascularization according to the angiosome concept is of proven importance for limb salvage in chronic limb threatening ischaemia but it is not always practicable....
OBJECTIVES
Revascularization according to the angiosome concept is of proven importance for limb salvage in chronic limb threatening ischaemia but it is not always practicable. Bifurcated bypasses could be considered as an option when an endovascular approach is not feasible or has already failed and a single bypass would not allow direct revascularization of the ischaemic area. Bifurcated bypasses are characterized by landing on two different arteries, the main artery (in direct continuity with the foot vessels) and the secondary one (perfusing the angiosome district). The aim of this study is to evaluate the safety and effectiveness of bifurcated bypass in chronic limb threatening ischaemia.
METHODS
Thirty-five patients were consecutively treated with a bifurcated bypass for chronic limb threatening ischaemia from January 2014 to December 2019 in a single vascular surgery centre. Data from clinical records and operative registers were collected prospectively in an electronic database and retrospectively analysed. Primary and primary assisted bypass patency, amputation-free survival, morbidity and mortality rates at 12 and 24 months were analysed.
RESULTS
Mean follow-up period was 25.1 months (range 2-72 months). Thirty-six bifurcated bypasses were performed on 35 patients (age 75.3 ± 7.2 years; 69.4% were male). According to Wound, Ischemia, foot Infection classification 22.2% belonged to stage 3 and 77.8% to stage 4 and the mean Rutherford's class was 5.1 ± 0.7. Immediate technical success was 100%. Early mortality and morbidity rates were respectively 5.5%, and 33.3%; foot surgery was performed in 50% of cases with wound healing in all patients. Primary patency and primary assisted bypass patency were 96.7% and 100% at 6 months; 85.2% and 92% at 12 months, 59.9% and 73.4% at 24 months, respectively. Amputation-free survival at 12 and 24 months was, respectively, 95.6% and 78.8%. Overall survival rates at 12 and 24 months were respectively 94.4% and 91.6%.
CONCLUSIONS
Bifurcates bypass can provide good results in patients with chronic limb threatening ischaemia without endovascular option, especially in diabetic ones. Bifurcated bypass is a complex surgical solution, both to be planned and performed, and it is quite invasive for frail patients that should be accurately selected.
Topics: Aged; Aged, 80 and over; Amputation, Surgical; Chronic Limb-Threatening Ischemia; Humans; Ischemia; Limb Salvage; Male; Peripheral Arterial Disease; Retrospective Studies; Risk Factors; Treatment Outcome; Vascular Patency
PubMed: 33691547
DOI: 10.1177/1708538121999856