-
The Journal of Cardiovascular Surgery Aug 2023Acute limb ischemia (ALI) is an emergency situation requiring rapid diagnosis and treatment. Although the traditional treating strategy for ALI includes open surgery,... (Review)
Review
Acute limb ischemia (ALI) is an emergency situation requiring rapid diagnosis and treatment. Although the traditional treating strategy for ALI includes open surgery, novel endovascular techniques have been introduced during the last decade. Additionally, many new cases of ALI have been reported due to infection by the SARS-CoV-2 virus. The aim of this study was to present an updated overview of characteristics, diagnosis, and current treating strategies of patients with ALI.
Topics: Humans; Limb Salvage; Treatment Outcome; Lower Extremity; Risk Factors; COVID-19; SARS-CoV-2; Peripheral Vascular Diseases; Endovascular Procedures; Ischemia; Acute Disease; Retrospective Studies
PubMed: 36762508
DOI: 10.23736/S0021-9509.22.12536-X -
The Surgical Clinics of North America Aug 2023The original description of the lower extremity bypass (LEB) provided surgeons with a reliable method of limb revascularization. The tenets of the operation have formed... (Review)
Review
The original description of the lower extremity bypass (LEB) provided surgeons with a reliable method of limb revascularization. The tenets of the operation have formed the foundation for the advances of surgical care. A careful evaluation of the chronic limb-threatening ischemia patient due to the numerous comorbid conditions is paramount to obtain the best possible outcomes. Use of all adjuncts including judicious target vessels control, completion imaging, and vein harvesting techniques to ensure optimal outcomes because a functioning LEB remains a key to successful limb salvage.
Topics: Humans; Ischemia; Risk Factors; Reoperation; Retrospective Studies; Lower Extremity; Treatment Outcome; Peripheral Arterial Disease; Saphenous Vein
PubMed: 37455036
DOI: 10.1016/j.suc.2023.04.014 -
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 -
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 -
Diabetologia Dec 2023Elevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population....
AIMS/HYPOTHESIS
Elevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. This association is not well studied in individuals with diabetes, who are often included in clinical trials of remnant cholesterol-lowering therapy. We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of ASCVD in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.
METHODS
We included 4569 white Danish individuals with diabetes (58% statin users) nested within the Copenhagen General Population Study (2003-2015). The ASCVDs peripheral artery disease, myocardial infarction and ischaemic stroke were extracted from national Danish health registries without losses to follow-up. Remnant cholesterol was calculated from a standard lipid profile.
RESULTS
During up to 15 years of follow-up, 236 individuals were diagnosed with peripheral artery disease, 234 with myocardial infarction, 226 with ischaemic stroke and 498 with any ASCVD. Multivariable adjusted HR (95% CI) per doubling of remnant cholesterol was 1.6 (1.1, 2.3; p=0.01) for peripheral artery disease, 1.8 (1.2, 2.5; p=0.002) for myocardial infarction, 1.5 (1.0, 2.1; p=0.04) for ischaemic stroke, and 1.6 (1.2, 2.0; p=0.0003) for any ASCVD. Excess risk conferred by diabetes was 2.5-fold for peripheral artery disease, 1.6-fold for myocardial infarction, 1.4-fold for ischaemic stroke and 1.6-fold for any ASCVD. Excess risk explained by elevated remnant cholesterol and low-grade inflammation was 14% and 8% for peripheral artery disease, 26% and 16% for myocardial infarction, 34% and 34% for ischaemic stroke, and 24% and 18% for any ASCVD, respectively. LDL-cholesterol did not explain excess risk, as it was not higher in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.
CONCLUSIONS/INTERPRETATION
Elevated remnant cholesterol was associated with increased risk of ASCVD in individuals with diabetes. Remnant cholesterol and low-grade inflammation explained substantial excess risk of ASCVD conferred by diabetes. Whether remnant cholesterol should be used as a treatment target remains to be determined in randomised controlled trials.
Topics: Humans; Cardiovascular Diseases; Prospective Studies; Brain Ischemia; Stroke; Atherosclerosis; Cholesterol; Diabetes Mellitus; Hypercholesterolemia; Inflammation; Myocardial Infarction; Peripheral Arterial Disease; Ischemic Stroke; Risk Factors
PubMed: 37776347
DOI: 10.1007/s00125-023-06016-0 -
Journal of the American College of... Jul 2023The impact of complete revascularization (CR) on angina-related health status (symptoms, function, quality of life) in chronic coronary disease (CCD) has not been well... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The impact of complete revascularization (CR) on angina-related health status (symptoms, function, quality of life) in chronic coronary disease (CCD) has not been well studied.
OBJECTIVES
Among patients with CCD randomized to invasive (INV) vs conservative (CON) management in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), we compared the following: 1) the impact of anatomic and functional CR on health status compared with incomplete revascularization (ICR); and 2) the predicted impact of achieving CR in all INV patients compared with CON.
METHODS
Multivariable regression adjusting for patient characteristics was used to compare 12-month health status after independent core laboratory-defined CR vs ICR in INV patients who underwent revascularization. Propensity-weighted modeling was then performed to estimate the treatment effect had CR or ICR been achieved in all INV patients, compared with CON.
RESULTS
Anatomic and functional CR were achieved in 43.3% and 57.8% of 1,641 INV patients, respectively. Among revascularized patients, CR was associated with improved Seattle Angina Questionnaire Angina Frequency compared with ICR after adjustment for baseline differences. After modeling CR and ICR in all INV patients, patients with CR and ICR each had greater improvements in health status than CON, with better health status with CR than ICR. The projected benefits of CR were most pronounced in patients with baseline daily/weekly angina and not seen in those with no angina.
CONCLUSIONS
Among patients with CCD in ISCHEMIA, health status improved more with CR compared with ICR or CON, particularly in those with frequent angina. Anatomic and functional CR provided comparable improvements in quality of life. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).
Topics: Humans; Quality of Life; Treatment Outcome; Angina Pectoris; Health Status; Myocardial Revascularization; Ischemia; Coronary Artery Disease
PubMed: 37468185
DOI: 10.1016/j.jacc.2023.05.025 -
Diabetes/metabolism Research and Reviews Mar 2024This publication represents a scheduled update of the 2019 guidelines of the International Working Group of the Diabetic Foot (IWGDF) addressing the use of systems to...
BACKGROUND
This publication represents a scheduled update of the 2019 guidelines of the International Working Group of the Diabetic Foot (IWGDF) addressing the use of systems to classify foot ulcers in people with diabetes in routine clinical practice. The guidelines are based on a systematic review of the available literature that identified 28 classifications addressed in 149 articles and, subsequently, expert opinion using the GRADE methodology.
METHODS
First, we have developed a list of classification systems considered as being potentially adequate for use in a clinical setting, through the summary of judgements for diagnostic tests, focussing on the usability, accuracy and reliability of each system to predict ulcer-related complications as well as use of resources. Second, we have determined, following group debate and consensus, which of them should be used in specific clinical scenarios. Following this process, in a person with diabetes and a foot ulcer we recommend: (a) for communication among healthcare professionals: to use the SINBAD (Site, Ischaemia, Bacterial infection, Area and Depth) system (first option) or consider using WIfI (Wound, Ischaemia, foot Infection) system (alternative option, when the required equipment and level of expertise is available and it is considered feasible) and in each case the individual variables that compose the systems should be described rather than a total score; (b) for predicting the outcome of an ulcer in a specific individual: no existing system could be recommended; (c) for characterising a person with an infected ulcer: the use of the IDSA/IWGDF classification (first option) or consider using the WIfI system (alternative option, when the required equipment and level of expertise is available and it is considered as feasible); (d) for characterising a person with peripheral artery disease: consider using the WIfI system as a means to stratify healing likelihood and amputation risk; (e) for the audit of outcome(s) of populations: the use of the SINBAD score.
CONCLUSIONS
For all recommendations made using GRADE, the certainty of evidence was judged, at best, as being low. Nevertheless, based on the rational application of current data this approach allowed the proposal of recommendations, which are likely to have clinical utility.
Topics: Humans; Diabetic Foot; Ulcer; Reproducibility of Results; Foot Ulcer; Ischemia; Diabetes Mellitus
PubMed: 37179483
DOI: 10.1002/dmrr.3648 -
International Journal of Molecular... Dec 2023This review will provide an overview of what is currently known about mechanisms linking poor glycaemic control with increased thrombotic risk. The leading causes of... (Review)
Review
This review will provide an overview of what is currently known about mechanisms linking poor glycaemic control with increased thrombotic risk. The leading causes of death in people with diabetes are strokes and cardiovascular disease. Significant morbidity is associated with an increased risk of thrombosis, resulting in myocardial infarction, ischaemic stroke, and peripheral vascular disease, along with the sequelae of these events, including loss of functional ability, heart failure, and amputations. While the increased platelet activity, pro-coagulability, and endothelial dysfunction directly impact this risk, the molecular mechanisms linking poor glycaemic control with increased thrombotic risk remain unclear. This review highlights the complex mechanisms underlying thrombosis prevalence in individuals with diabetes and hyperglycaemia. Post-translational modifications, such as O-GlcNAcylation, play a crucial role in controlling protein function in diabetes. However, the role of O-GlcNAcylation remains poorly understood due to its intricate regulation and the potential involvement of multiple variables. Further research is needed to determine the precise impact of O-GlcNAcylation on specific disease processes.
Topics: Humans; Brain Ischemia; Stroke; Diabetes Mellitus; Thrombosis; Myocardial Infarction; Hyperglycemia
PubMed: 38139295
DOI: 10.3390/ijms242417465 -
Nature Communications Nov 2023Ischaemia of the heart and limbs attributable to compromised blood supply is a major cause of mortality and morbidity. The mechanisms of functional angiogenesis remain...
Ischaemia of the heart and limbs attributable to compromised blood supply is a major cause of mortality and morbidity. The mechanisms of functional angiogenesis remain poorly understood, however. Here we show that FNIP1 plays a critical role in controlling skeletal muscle functional angiogenesis, a process pivotal for muscle revascularization during ischemia. Muscle FNIP1 expression is down-regulated by exercise. Genetic overexpression of FNIP1 in myofiber causes limited angiogenesis in mice, whereas its myofiber-specific ablation markedly promotes the formation of functional blood vessels. Interestingly, the increased muscle angiogenesis is independent of AMPK but due to enhanced macrophage recruitment in FNIP1-depleted muscles. Mechanistically, myofiber FNIP1 deficiency induces PGC-1α to activate chemokine gene transcription, thereby driving macrophage recruitment and muscle angiogenesis program. Furthermore, in a mouse hindlimb ischemia model of peripheral artery disease, the loss of myofiber FNIP1 significantly improved the recovery of blood flow. Thus, these results reveal a pivotal role of FNIP1 as a negative regulator of functional angiogenesis in muscle, offering insight into potential therapeutic strategies for ischemic diseases.
Topics: Mice; Animals; Mice, Knockout; Mice, Inbred C57BL; Muscle, Skeletal; Macrophages; Disease Models, Animal; Ischemia; Hindlimb; Neovascularization, Physiologic; Carrier Proteins
PubMed: 37932296
DOI: 10.1038/s41467-023-42690-9 -
Journal of Neuroinflammation Nov 2023Emerging evidence has shown that myeloid cells that infiltrate into the peri-infarct region may influence the progression of ischemic stroke by interacting with...
BACKGROUND
Emerging evidence has shown that myeloid cells that infiltrate into the peri-infarct region may influence the progression of ischemic stroke by interacting with microglia. Properdin, which is typically secreted by immune cells such as neutrophils, monocytes, and T cells, has been found to possess damage-associated molecular patterns (DAMPs) properties and can perform functions unrelated to the complement pathway. However, the role of properdin in modulating microglia-mediated post-stroke neuroinflammation remains unclear.
METHODS
Global and conditional (myeloid-specific) properdin-knockout mice were subjected to transient middle cerebral artery occlusion (tMCAO). Histopathological and behavioral tests were performed to assess ischemic brain injury in mice. Single-cell RNA sequencing and immunofluorescence staining were applied to explore the source and the expression level of properdin. The transcriptomic profile of properdin-activated primary microglia was depicted by transcriptome sequencing. Lentivirus was used for macrophage-inducible C-type lectin (Mincle) silencing in microglia. Conditioned medium from primary microglia was administered to primary cortex neurons to determine the neurotoxicity of microglia. A series of cellular and molecular biological techniques were used to evaluate the proinflammatory response, neuronal death, protein-protein interactions, and related signaling pathways, etc. RESULTS: The level of properdin was significantly increased, and brain-infiltrating neutrophils and macrophages were the main sources of properdin in the ischemic brain. Global and conditional myeloid knockout of properdin attenuated microglial overactivation and inflammatory responses at the acute stage of tMCAO in mice. Accordingly, treatment with recombinant properdin enhanced the production of proinflammatory cytokines and augmented microglia-potentiated neuronal death in primary culture. Mechanistically, recombinant properdin served as a novel ligand that activated Mincle receptors on microglia and downstream pathways to drive primary microglia-induced inflammatory responses. Intriguingly, properdin can directly bind to the microglial Mincle receptor to exert the above effects, while Mincle knockdown limits properdin-mediated microglial inflammation.
CONCLUSION
Properdin is a new medium by which infiltrating peripheral myeloid cells communicate with microglia, further activate microglia, and exacerbate brain injury in the ischemic brain, suggesting that targeted disruption of the interaction between properdin and Mincle on microglia or inhibition of their downstream signaling may improve the prognosis of ischemic stroke.
Topics: Mice; Animals; Microglia; Ischemic Stroke; Properdin; Neuroinflammatory Diseases; Macrophages; Infarction, Middle Cerebral Artery; Brain Injuries; Brain Ischemia; Mice, Inbred C57BL
PubMed: 37951917
DOI: 10.1186/s12974-023-02946-z