Intraluminal oxygen can keep small bowel mucosa intact in a segmental ischemia model.

Intestinal preservation for transplantation is accompanied by hypoperfusion with long periods of ischemia with total blood cessation and absolute withdrawal of oxygen leading to structural damage. The application of intraluminal oxygen has been successfully tested in small-animal series during storage and transport of the organ but have been so far clinically unrelatable. In this study, we tested whether a simple and clinically approachable method of intraluminal oxygen application could prevent ischemic damage in a large animal model, during warm ischemia time. We utilised a local no-flow ischemia model of the small intestine in pigs. A low-flow and high-pressure intraluminal oxygen deliverance system was applied in 6 pigs and 6 pigs served as a control group. Mucosal histopathology, hypoxia and barrier markers were evaluated after two hours of no-flow conditions, in both treatment and sham groups, and in healthy tissue. Macro- and microscopically, the luminal oxygen delivered treatment group showed preserved small bowel's appearance, viability, and mucosal integrity. A gradual deterioration of histopathology and barrier markers and increase in hypoxia-inducible factor 1-α expression towards the sites most distant from the oxygen application was observed. Intraluminal low-flow, high oxygen delivery can preserve the intestinal mucosa during total ischemia of the small intestine. This finding can be incorporated in methods to overcome small bowel ischemia and improve intestinal preservation for transplantation.

A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb.

Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were elevated in patients with chronic limb-threatening ischemia (CLTI), and these amounts decreased after revascularization. Unlike CD16-negative monocytes, PAMs showed large vessel remodeling properties in vitro when cultured with endothelial cells and smooth muscle cells and promoted salvage of the ischemic limb in vivo in a mouse model of hindlimb ischemia. PAMs showed a propensity to migrate toward and bind to ischemic muscle and to secrete angiogenic/arteriogenic factors, vascular endothelial growth factor A (VEGF-A) and heparin-binding epidermal growth factor. We instigated a first-in-human single-arm cohort study in which autologous PAMs were injected into the ischemic limbs of five patients with CLTI. Greater than 25% of injected cells were retained in the leg for at least 72 hours, of which greater than 80% were viable, with evidence of enhanced large vessel remodeling in the injected muscle area. In summary, we identified up-regulation of a circulatory PAM subpopulation as an endogenous response to limb ischemia in CLTI and tested a potentially clinically relevant therapeutic strategy.

Use of carbon dioxide fractional laser in the management of lower limb ischemia in patients with diabetes: a case report : CO2 fractional laser in the treatment of diabetic foot.

Treatment of lower limb ischemia in patients with diabetes is challenging because of the location of the ulcers and the complexity of their pathogenesis. Carbon dioxide fractional laser (CO2FL) therapy in conjunction with tibial periosteum distraction could become a substitute for conventional methods. We herein describe a patient diagnosed with ischemic diabetic foot with a complex ulcer in the upper third of the tibia. Laser irradiation (Deep FX mode with 30 mJ of energy and 10% density) was applied to the entire region of skin below the knee after surface anesthesia, and this treatment was performed twice a week until the ulcer healed. Computed tomography angiography showed successful establishment of a blood supply to the back of the right foot after treatment. Skin grafting was successfully performed, with only a few wounds remaining on the foot 8 months after treatment. The pain score was significantly decreased at the last follow-up. No complications occurred. This case report provides guidance for the performance of CO2FL, a fast, easy, accurate treatment in patients with diabetes. CO2FL can target lower limb arterial occlusive disease accompanied by refractory ulcers, addressing the underlying vascular occlusion and dysfunction as well as promoting microcirculation and wound healing.

Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.

Ischaemic diseases such as critical limb ischaemia and myocardial infarction affect millions of people worldwide1. Transplanting endothelial cells (ECs) is a promising therapy in vascular medicine, but engrafting ECs typically necessitates co-transplanting perivascular supporting cells such as mesenchymal stromal cells (MSCs), which makes clinical implementation complicated2,3. The mechanisms that enable MSCs to facilitate EC engraftment remain elusive. Here we show that, under cellular stress, MSCs transfer mitochondria to ECs through tunnelling nanotubes, and that blocking this transfer impairs EC engraftment. We devised a strategy to artificially transplant mitochondria, transiently enhancing EC bioenergetics and enabling them to form functional vessels in ischaemic tissues without the support of MSCs. Notably, exogenous mitochondria did not integrate into the endogenous EC mitochondrial pool, but triggered mitophagy after internalization. Transplanted mitochondria co-localized with autophagosomes, and ablation of the PINK1-Parkin pathway negated the enhanced engraftment ability of ECs. Our findings reveal a mechanism that underlies the effects of mitochondrial transfer between mesenchymal and endothelial cells, and offer potential for a new approach for vascular cell therapy.

Gold Nanorod-Loaded Nano-Contrast Agent with Composite Shell-Core Structure for Ultrasonic/Photothermal Imaging-Guided Therapy in Ischemic Muscle Disorders.

Purpose: This study aims to broaden the application of nano-contrast agents (NCAs) within the realm of the musculoskeletal system. It aims to introduce novel methods, strategies, and insights for the clinical management of ischemic muscle disorders, encompassing diagnosis, monitoring, evaluation, and therapeutic intervention. Methods: We developed a composite encapsulation technique employing O-carboxymethyl chitosan (OCMC) and liposome to encapsulate NCA-containing gold nanorods (GNRs) and perfluoropentane (PFP). This nanoscale contrast agent was thoroughly characterized for its basic physicochemical properties and performance. Its capabilities for in vivo and in vitro ultrasound imaging and photothermal imaging were authenticated, alongside a comprehensive biocompatibility assessment to ascertain its effects on microcirculatory perfusion in skeletal muscle using a murine model of hindlimb ischemia, and its potential to augment blood flow and facilitate recovery. Results: The engineered GNR@OCMC-liposome/PFP nanostructure exhibited an average size of 203.18±1.49 nm, characterized by size uniformity, regular morphology, and a good biocompatibility profile. In vitro assessments revealed NCA's potent photothermal response and its transformation into microbubbles (MBs) under near-infrared (NIR) irradiation, thereby enhancing ultrasonographic visibility. Animal studies demonstrated the nanostructure's efficacy in photothermal imaging at ischemic loci in mouse hindlimbs, where NIR irradiation induced rapid temperature increases and significantly increased blood circulation. Conclusion: The dual-modal ultrasound/photothermal NCA, encapsulating GNR and PFP within a composite shell-core architecture, was synthesized successfully. It demonstrated exceptional stability, biocompatibility, and phase transition efficiency. Importantly, it facilitates the encapsulation of PFP, enabling both enhanced ultrasound imaging and photothermal imaging following NIR light exposure. This advancement provides a critical step towards the integrated diagnosis and treatment of ischemic muscle diseases, signifying a pivotal development in nanomedicine for musculoskeletal therapeutics.

Understanding delays in chronic limb-threatening ischaemia care: Application of the theoretical domains framework to identify factors affecting primary care clinicians' referral behaviours.

INTRODUCTION: Patients in the community with suspected Chronic limb-threatening ischaemia (CLTI) should be urgently referred to vascular services for investigation and management. The Theoretical Domains Framework (TDF) allows identification of influences on health professional behaviour in order to inform future interventions. Here, the TDF is used to explore primary care clinicians' behaviours with regards to recognition and referral of CLTI. METHODS: Semi-structured interviews were conducted with 20 podiatrists, nurses and general practitioners in primary care. Directed content analysis was performed according to the framework method. Utterances were coded to TDF domains, and belief statements were defined by grouping similar utterances. Relevance of domains was confirmed according to belief frequency, presence of conflicting beliefs and the content of the beliefs indicating relevance. RESULTS: Nine TDF domains were identified as relevant to primary care clinicians: Knowledge, Environmental context and resources, Memory, Decision and attention processes, Beliefs about capabilities, Skills, Emotions, Reinforcement and Behavioural regulation. Relationships across domains were identified, including how primary care clinician confidence and working in a highly pressurized environment can affect behaviour. CONCLUSION: We have identified key barriers and enablers to timely recognition and referral behaviour. These beliefs identify targets for theory-driven behaviour change interventions to reduce delays in CLTI pathways.

The Evaluation and Management of Intestinal Ischemia.

AbstractIntestinal ischemia can result from various pathologic conditions. The presentations of ischemia can range from acute to subacute and mild to severe. Diagnosis of this condition may pose challenges, particularly in the early, potentially salvageable, stages of disease. This review offers an evidence-based approach to understanding the diagnosis and management of inadequate intestinal perfusion.

3D-Printed proangiogenic patches of photo-crosslinked gelatin and polyurethane hydrogels laden with vascular cells for treating vascular ischemic diseases.

Engineering vascularized tissues remains a promising approach for treating ischemic cardiovascular diseases. The availability of 3D-bioprinted vascular grafts that induce therapeutic angiogenesis can help avoid necrosis and excision of ischemic tissues. Here, using a combination of living cells and biodegradable hydrogels, we fabricated 3D-printed biocompatible proangiogenic patches from endothelial cell-laden photo-crosslinked gelatin (EC-PCG) bioink and smooth muscle cell-encapsulated polyurethane (SMC-PU) bioink. Implantation of 3D-bioprinted proangiogenic patches in a mouse model showed that EC-PCG served as an angiogenic capillary bed, whereas patterned SMC-PU increased the density of microvessels. Moreover, the assembled patterns between EC-PCG and SMC-PU induced the geometrically guided generation of microvessels with blood perfusion. In a rodent model of hindlimb ischemia, the vascular patches rescued blood flow to distal tissues, prevented toe/foot necrosis, promoted muscle remodeling, and increased the capillary density, thereby improving the heat-escape behavior of ischemic animals. Thus, our 3D-printed vascular cell-laden bioinks constitute efficient and scalable biomaterials that facilitate the engineering of vascular patches capable of directing therapeutic angiogenesis for treating ischemic vascular diseases.

Therapeutic Effects of Anti-Inflammatory and Anti-Oxidant Nutritional Supplementation in Retinal Ischemic Diseases.

Appropriate nutrients are essential for cellular function. Dietary components can alter the risk of systemic metabolic diseases, including cardiovascular diseases, cancer, diabetes, and obesity, and can also affect retinal diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. Dietary nutrients have been assessed for the prevention or treatment of retinal ischemic diseases and the diseases of aging. In this article, we review clinical and experimental evidence concerning the potential of some nutritional supplements to prevent or treat retinal ischemic diseases and provide further insights into the therapeutic effects of nutritional supplementation on retinopathies. We will review the roles of nutrients in preventing or protecting against retinal ischemic diseases.

Systematic review and meta-analysis of the effect of bone marrow-derived cell therapies on hind limb perfusion.

Preclinical and clinical studies on the administration of bone marrow-derived cells to restore perfusion show conflicting results. We conducted a systematic review and meta-analysis on preclinical studies to assess the efficacy of bone marrow-derived cells in the hind limb ischemia model and identify possible determinants of therapeutic efficacy. In vivo animal studies were identified using a systematic search in PubMed and EMBASE on 10 January 2022. 85 studies were included for systematic review and meta-analysis. Study characteristics and outcome data on relative perfusion were extracted. The pooled mean difference was estimated using a random effects model. Risk of bias was assessed for all included studies. We found a significant increase in perfusion in the affected limb after administration of bone marrow-derived cells compared to that in the control groups. However, there was a high heterogeneity between studies, which could not be explained. There was a high degree of incomplete reporting across studies. We therefore conclude that the current quality of preclinical research is insufficient (low certainty level as per GRADE assessment) to identify specific factors that might improve human clinical trials.

Alginate-Encapsulated Mesenchymal Stromal Cells Improve Hind Limb Ischemia in a Translational Swine Model.

BACKGROUND: Cellular therapies have been investigated to improve blood flow and prevent amputation in peripheral artery disease with limited efficacy in clinical trials. Alginate-encapsulated mesenchymal stromal cells (eMSCs) demonstrated improved retention and survival and promoted vascular generation in murine hind limb ischemia through their secretome, but large animal evaluation is necessary for human applicability. We sought to determine the efficacy of eMSCs for peripheral artery disease-induced limb ischemia through assessment in our durable swine hind limb ischemia model. METHODS AND RESULTS: Autologous bone marrow eMSCs or empty alginate capsules were intramuscularly injected 2 weeks post-hind limb ischemia establishment (N=4/group). Improvements were quantified for 4 weeks through walkway gait analysis, contrast angiography, blood pressures, fluorescent microsphere perfusion, and muscle morphology and histology. Capsules remained intact with mesenchymal stromal cells retained for 4 weeks. Adenosine-induced perfusion deficits and muscle atrophy in ischemic limbs were significantly improved by eMSCs versus empty capsules (mean±SD, 1.07±0.19 versus 0.41±0.16, P=0.002 for perfusion ratios and 2.79±0.12 versus 1.90±0.62 g/kg, P=0.029 for ischemic muscle mass). Force- and temporal-associated walkway parameters normalized (ratio, 0.63±0.35 at week 3 versus 1.02±0.19 preligation; P=0.17), and compensatory footfall patterning was diminished in eMSC-administered swine (12.58±8.46% versus 34.85±15.26%; P=0.043). Delivery of eMSCs was associated with trending benefits in collateralization, local neovascularization, and muscle fibrosis. Hypoxia-cultured porcine mesenchymal stromal cells secreted vascular endothelial growth factor and tissue inhibitor of metalloproteinase 2. CONCLUSIONS: This study demonstrates the promise of the mesenchymal stromal cell secretome at improving peripheral artery disease outcomes and the potential for this novel swine model to serve as a component of the preclinical pipeline for advanced therapies.

Ocular Ischemic Syndrome and the Role of Carotid Artery Revascularization.

BACKGROUND: Ocular ischemic syndrome (OIS) is a rare presentation of atherosclerotic carotid artery stenosis that can result in permanent visual loss. This severely disabling syndrome remains under diagnosed and undertreated due to lack of awareness; especially since it requires expedited multidisciplinary care. The relevance of early diagnosis and treatment is increasing due to an increasing prevalence of cerebrovascular disease. METHODS: The long-term visual and cerebrovascular outcomes following intervention for nonarteritic OIS, remain poorly described and were the objective of this concise review. We conducted a PubMed search to include all English language publications (cohort studies and case reports) between 2002 and 2023. RESULTS: A total of 33 studies (479 patients) report the outcomes of treatment of OIS with carotid endarterectomy (CEA, 304 patients, 19 studies), and carotid artery stenting (CAS, 175 patients, 14 studies). Visual outcomes were improved or did not worsen in 447 patients (93.3%). No periprocedural stroke was reported. Worsening visual symptoms were rare (35 patients, 7.3%); they occurred in the immediate postoperative period secondary to ocular hypoperfusion (3 patients) and in the late postoperative period due to progression of systemic atherosclerotic disease. Symptomatic recurrence due to recurrent stenosis after CEA was reported in 1 patient (0.21%); this was managed successfully with CAS. None of these studies report the results of transcarotid artery revascularization, the long-term operative outcome or stroke rate. CONCLUSIONS: OIS remains to be an underdiagnosed condition. Early diagnosis and prompt treatment are crucial in reversal or stabilization of OIS symptoms. An expedited multidisciplinary approach between vascular surgery and ophthalmology services is necessary to facilitate timely treatment and optimize outcome. If diagnosed early, both CEA and CAS have been associated with visual improvement and prevention of progressive visual loss.

Acute aortic occlusion: A narrative review for emergency clinicians.

INTRODUCTION: Acute aortic occlusion (AAO) is a rare but serious condition associated with significant morbidity and mortality. OBJECTIVE: This review provides an emergency medicine focused evaluation of AAO, including presentation, assessment, and emergency department (ED) management based on current evidence. DISCUSSION: AAO refers to obstruction of blood flow through the aorta due to either thrombosis or embolism. This condition primarily affects older adults ages 60-70 with cardiovascular comorbidities and most commonly presents with signs and symptoms of acute limb ischemia, though the gastrointestinal tract, kidneys, and spinal cord may be affected. The first line imaging modality includes computed tomography angiography of the chest, abdomen, and pelvis. ED resuscitative management consists of avoiding extremes of blood pressure or heart rate, maintaining normal oxygen saturation and euvolemic status, anticoagulation with heparin, and pain control. Emergent consultation with the vascular surgery specialist is recommended to establish a plan for restoration of perfusion to ischemic tissues via endovascular or open techniques. High rates of baseline comorbidities present in the affected population as well as ischemic and reperfusion injuries place AAO patients at high risk for complications in an immediate and delayed fashion after surgical management. CONCLUSIONS: An understanding of AAO can assist emergency clinicians in diagnosing and managing this rare but devastating disease.

Performance of drug-coated balloons in coronary and below-the-knee arteries: Anatomical, physiological and pathological considerations.

Below-the-knee (infrapopliteal) atherosclerotic disease, which presents as chronic limb-threatening ischemia (CLTI) in nearly 50% of patients, represents a treatment challenge when it comes to the endovascular intervention arm of management. Due to reduced tissue perfusion, patients usually experience pain at rest and atrophic changes correlated to the extent of the compromised perfusion. Unfortunately, the prognosis remains unsatisfactory with 30% of patients requiring major amputation and a mortality rate of 25% within 1 year. To date, randomized multicentre trials of endovascular intervention have shown that drug-eluting stents (DES) increase patency rate and lower target lesion revascularization rate compared to plain balloon angioplasty and bare-metal stents. The majority of these trials recruited patients with focal infrapopliteal lesions, while most patients requiring endovascular intervention have complex and diffuse atherosclerotic disease. Moreover, due to the nature of the infrapopliteal arteries, the use of long DES is limited. Following recent results of drug-coated balloons (DCBs) in the treatment of femoropopliteal and coronary arteries, it was hoped that similar effective results would be achieved in the infrapopliteal arteries. In reality, multicentre trials have failed to support the proposed hypothesis and no advantage was found in using DCBs in comparison to plain balloon angioplasty. This review aims to explore anatomical, physiological and pathological differences between lesions of the infrapopliteal and coronary arteries to explain the differences in outcome when using DCBs.

Outcomes of Alprostadil As an Adjuvant Therapy with Indirect Angiosomal Revascularization in Patients with Critical Limb Ischemia after Failure of Direct Revascularization.

BACKGROUND: This study was carried out to assess the effectiveness of alprostadil (prostaglandin E1) when used as an adjuvant therapy with indirect revascularization in patients with critical limb ischemia (CLI) after the failure of direct revascularization (DR). METHODS: At our centers, 120 patients suffering from infrainguinal peripheral arterial disease with CLI underwent a failed trial of DR procedure, all revascularization procedures were endovascular. Median follow-up was 2 years and 2.5 years for patients with and without diabetes mellitus (DM). In the alprostadil group, the mean age was 63.41 ± 12.52; 36 (60%) for males and 24 (40%) for females. Post-endovascular intervention alprostadil was administrated immediately postoperatively by intravenous infusion of 40 µg alprostadil diluted in 100 ml of normal saline, over 2 hr every 12 hr for 6 days. RESULTS: In the alprostadil group, the mean ± standard deviation (SD) of the baseline ankle-brachial index (ABI) was 0.45 ± 0.175, while the mean ± SD of ABI at the end of our study was 0.65 ± 0.216 with a difference from the baseline of 0.2 ± 0.041 (P value = 0.08, <0.05 meaning that it is significant). Our 1-month primary patency rate was 93.3%, while our 3- and 6-month patency rate was 92.9%. In the control group, the mean ± SD of the baseline ABI was 0.68 ± 0.22, while the mean ± SD of ABI at the end of our study was 0.69 ± 0.23 with a difference from the baseline of 0.01 ± 0.01 (P value >0.05 meaning that it is nonsignificant) 1-month patency rate was 89%, while 3- and 6-month patency rate was 75%. When we compared the patient's leg vessels before and after our intervention, we found that the percentage of the no-runoff-vessels group decreased from 10 (16.7%) to 4 (6.67%). One-runoff-vessel group percentage dropped from 40 (66.7%) to 36 (60%), whereas, in the two-runoff-vessel group, the percentage increased from 10 (16.7%) to 20 (33.3%). We evaluate leg arteries; we do no pedal arch intervention in the alpostradil group. Out of the total of 60 patients, limb salvage occurred in 58 (96.7%) patients, and 2 (3.3%) patients underwent below-the-knee amputation before the study ended. CONCLUSIONS: Our results show the efficacy and safety of alprostadil as an adjuvant therapy with indirect angiosomal revascularization in patients with tissue loss due to CLI.

Impact of hyperuricemia on 5-year clinical outcomes in patients with critical limb ischemia following percutaneous transluminal angioplasty.

BACKGROUND: A growing evidence on the correlation between hyperuricemia and cardiovascular disease (CVD) has been previously reported. However, there have been limited data on the impact of hyperuricemia on long-term clinical outcomes in patients with critical limb ischemia (CLI) who underwent percutaneous transluminal angioplasty (PTA). METHODS: A total of 425 peripheral artery disease patients who underwent PTA for CLI were enrolled. The patients were divided into the hyperuricemia group (n = 101) and the normal group (n = 324). The primary endpoint was major adverse cerebral and cardiovascular event (MACCE), including death, myocardial infarction, any coronary revascularization, and stroke, up to 5 years. The secondary endpoint was a major adverse limb event (MALE), including any repeated PTA, and target extremity surgery. Inverse probability weighting (IPTW) analysis, derived from the logistic regression model, was performed to adjust for potential confounders. RESULTS: After IPTW matching analysis, compared to the normal group, the hyperuricemia group was associated with a higher incidence of MACCE (20.7% vs. 13.6%, hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.15-2.38, P  = 0.006) including non-cardiac death (11.7% vs. 6.3%, HR: 1.95, 95% CI: 1.19-3.19, P  = 0.006) and MALE (47.7% vs. 36.0%, HR: 1.62, 95% CI: 1.23-2.13, P  = 0.001) including non-target extremity revascularization (15.0% vs. 6.8%, HR: 2.42, 95% CI: 1.52-3.84, P  < 0.001). CONCLUSION: In the present study, hyperuricemia was associated with worse clinical outcomes in patients with CLI following PTA during 5-year clinical follow-up. Efficacy of controlling hyperuricemia in improving clinical outcomes should be evaluated in further studies.

The effect of hyperbaric oxygen therapy on hematological indices and biochemical parameters in patients with diabetic foot.

BACKGROUND: Diabetes Mellitus (DM) is a metabolic disease with a high morbidity and mortality and increasing in prevalence all over the world. Due to the hypoxic, ischemic, inflammatory, and infective environment in DM, diabetic foot ulcers have been treated with medico-surgical interventions and adjuvant hyperbaric oxygen Therapy (HBOT). The purpose of this study was to evaluate the effects of HBOT on hematological indices and biochemical parameters in patients with diabetic foot. METHODS: The study group was formed from the file records of 103 male patients who applied to Yunus Emre State Hospital HBOT Center between September 1, 2016 and December 31, 2020, and were treated HBOT with a multidisciplinary approach. RESULTS: There were negative low correlations between number of HBOT sessions and Mean Corpuscular Hemoglobin (MCH) (P = .037, r = -0.207) and Blood Urea Nitrogen (BUN) (P = .037, r = -0.222). White Blood Cell Count (WBC), Neutrophils (NEU), Monocytes (MON), Platelet Count (PLT), and Plateletcrit (PTC) parameters were found to be decreased, and an increase in lymphocytes (LYM), Eosinophils (EOS), Mean Corpuscular Hemoglobin Concentration (MCHC), and Red Cell Distribution Width (RDW) parameters were detected after the treatments (P < .05). Again, after the treatment, glucose (Glu), C-Reactive Protein (CRP), direct bilirubin, and total protein (TP) levels were decreased, and uric acid (UA) levels increased (P < .05). CONCLUSION: HBOT improved hematological indices in patients and had a beneficial effect on biochemical parameters, particularly Glu and CRP levels. Adjuvant HBOT alleviates diabetic inflammation and has a beneficial effect on diabetic patient treatment.

What Is Priapism?

This JAMA Patient Page describes the diagnosis, prevention, and treatment of priapism.