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Development of a two-stage limb ischemia model to better simulate human peripheral artery disease.

ABSTRACT: Peripheral arterial disease (PAD) develops due to the narrowing or blockage of arteries supplying blood to the lower limbs. Surgical and endovascular interventions are the main treatments for advanced PAD but alternative and adjunctive medical therapies are needed. Currently the main preclinical experimental model employed in PAD research is based on induction of acute hind limb ischemia (HLI) by a 1-stage procedure. Since there are concerns regarding the ability to translate findings from this animal model to patients, we aimed to develop a novel clinically relevant animal model of PAD. HLI was induced in male Apolipoprotein E (ApoE-/-) deficient mice by a 2-stage procedure of initial gradual femoral artery occlusion by ameroid constrictors for 14 days and subsequent excision of the femoral artery. This 2-stage HLI model was compared to the classical 1-stage HLI model and sham controls. Ischemia severity was assessed using Laser Doppler Perfusion Imaging (LDPI). Ambulatory ability was assessed using an open field test, a treadmill test and using established scoring scales. Molecular markers of angiogenesis and shear stress were assessed within gastrocnemius muscle tissue samples using quantitative polymerase chain reaction. HLI was more severe in mice receiving the 2-stage compared to the 1-stage ischemia induction procedure as assessed by LDPI (p?=?0.014), and reflected in a higher ischemic score (p?=?0.004) and lower average distance travelled on a treadmill test (p?=?0.045). Mice undergoing the 2-stage HLI also had lower expression of angiogenesis markers (vascular endothelial growth factor, p?=?0.004; vascular endothelial growth factor- receptor 2, p?=?0.008) and shear stress response mechano-transducer transient receptor potential vanilloid 4 (p?=?0.041) within gastrocnemius muscle samples, compared to animals having the 1-stage HLI procedure. Mice subjected to the 2-stage HLI receiving an exercise program showed significantly greater improvement in their ambulatory ability on a treadmill test than a sedentary control group. This study describes a novel model of HLI which leads to more severe and sustained ischemia than the conventionally used model. Exercise therapy, which has established efficacy in PAD patients, was also effective in this new model. This new model maybe useful in the evaluation of potential novel PAD therapies.

SUBMITTER: Krishna SM

PROVIDER: S-EPMC7044206 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Development of a two-stage limb ischemia model to better simulate human peripheral artery disease.

Krishna Smriti M SM Omer Safraz Mohamed SM Li Jiaze J Morton Susan K SK Jose Roby J RJ Golledge Jonathan J

Scientific reports 20200226 1

Peripheral arterial disease (PAD) develops due to the narrowing or blockage of arteries supplying blood to the lower limbs. Surgical and endovascular interventions are the main treatments for advanced PAD but alternative and adjunctive medical therapies are needed. Currently the main preclinical experimental model employed in PAD research is based on induction of acute hind limb ischemia (HLI) by a 1-stage procedure. Since there are concerns regarding the ability to translate findings from this ...[more]

PMID: 32103073

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Project description:BackgroundFollowing severe limb ischemia requiring urgent/emergent revascularization, peripheral arterial disease patients suffer a high risk of recurrent atherothrombosis.MethodsPatients discharged from Hamilton General Hospital (Hamilton, Ontario) between April 2016 and September 2017 following severe limb ischemia requiring urgent/emergent revascularization were identified via the Local Health Integration Network CorHealth database, with supplemental information from chart review.ResultsA total of 158 patients admitted for urgent/emergent revascularization were identified (148 alive at discharge). Among patients without a pre-existing indication for anticoagulation, 38.8% (n = 47) were discharged on single-antiplatelet therapy, 27.3% (n = 33) on dual-antiplatelet therapy, 19.8% (n = 24) on anticoagulants plus antiplatelet therapy, 6.6% (n = 8) on anticoagulants alone, and 2.6% (n = 3) on unknown therapy. Patients who received angioplasty with stenting were more likely be discharged on dual-antiplatelet therapy (hazard ratio [HR]: 7.14; 95% confidence interval [CI]: 2.87-17.76; P < 0.01); patients who received an embolectomy/thrombectomy were more likely be discharged on an anticoagulant alone (HR: 2.61; 95% CI: 1.00-6.81; P = 0.049); and patients who received peripheral bypass grafting were more likely be discharged on single-antiplatelet therapy (HR: 2.28; 95% CI: 1.11-4.69; P = 0.024). Neither statins (60.8% vs 56.3%; P = 0.23) nor renin-angiotensin-aldosterone system inhibitors (48.7% vs 50.6%; P = 0.58) were prescribed at higher rates at discharge, compared with the rate at admission.ConclusionsSubstantial heterogeneity exists in antithrombotic prescription following urgent/emergent revascularization. No intensification of non-antithrombotic vascular protective medications occurred during hospitalization. Clinical trials and health system interventions to optimize medical therapy in peripheral arterial disease patients are urgently needed.

Project description:Fewer than half of individuals with peripheral artery disease (PAD) experience classic claudication, and the relationships between PAD typical or atypical symptom intensity, location, and description (classic or atypical) with ischemic changes have not previously been reported.The primary purpose of this study was to evaluate the relationship between self-reported PAD symptom intensity and calf tissue ischemia measured using the tissue saturation index (TSI) during treadmill exercise. The location and descriptors of atypical PAD symptoms in the presence of calf tissue ischemia were also identified.Adults with PAD with exercise-limiting ischemic symptoms were asked to (a) rate symptom intensity using a numerical rating scale (NRS) from 0 to 5 (0 = no pain, 1 = onset of pain, 5 = maximal pain), (b) provide symptom locations and descriptors, and (c) wear a near-infrared spectroscopy device to obtain calf TSI values during treadmill exercise. Multilevel models with TSI as the outcome variable were estimated during exercise and recovery. Covariates included were exercise time, recovery time, baseline TSI, exercise rating, recovery rating, ankle-brachial index (ABI), age, race, gender, body mass index, diabetes, neuropathy, and smoking.During three successive bouts of treadmill exercise for 40 participants (80% Caucasian men; average age = 68 years, SD = 9.2), the most rapid decline in TSI occurred between the start of exercise and symptom onset (when NRS = 1). The TSI nadir was often reached prior to report of maximum discomfort (when NRS = 5), and changes in TSI were related to exercise time (p < .001), baseline TSI (p < .001), exercise ratings (p < .001), and ABI (p < .05). During recovery, TSI increased steadily for most participants as pain eased. In the recovery model, changes in TSI were associated with recovery ratings (p < .001) and ABI (p < .03). Of 120 treadmill exercise tests, 69.2% were stopped due to discomfort in the calf with classic descriptors reported only half the time (55.4%).Exploratory analyses revealed ischemic symptoms extended beyond classic claudication locations and descriptors. Future research should evaluate changes in TSI relative to atypical locations and descriptors to improve understanding of the full range of ischemic symptoms experienced by individuals with PAD.

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Development of a two-stage limb ischemia model to better simulate human peripheral artery disease.

Publications

Development of a two-stage limb ischemia model to better simulate human peripheral artery disease.

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