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Abnormal Microvascular Architecture, Fibrosis, and Pericyte Characteristics in the Calf Muscle of Peripheral Artery Disease Patients with Claudication and Critical Limb Ischemia.

ABSTRACT: Work from our laboratory documents pathological events, including myofiber oxidative damage and degeneration, myofibrosis, micro-vessel (diameter = 50-150 ?m) remodeling, and collagenous investment of terminal micro-vessels (diameter ? 15 µm) in the calf muscle of patients with Peripheral Artery Disease (PAD). In this study, we evaluate the hypothesis that the vascular pathology associated with the legs of PAD patients encompasses pathologic changes to the smallest micro-vessels in calf muscle. Biopsies were collected from the calf muscle of control subjects and patients with Fontaine Stage II and Stage IV PAD. Slide specimens were evaluated by Quantitative Multi-Spectral and Fluorescence Microscopy. Inter-myofiber collagen, stained with Masson Trichrome (MT), was increased in Stage II patients, and more substantially in Stage IV patients in association with collagenous thickening of terminal micro-vessel walls. Evaluation of the Basement Membrane (BM) of these vessels reveals increased thickness in Stage II patients, and increased thickness, diameter, and Collagen I deposition in Stage IV patients. Coverage of these micro-vessels with pericytes, key contributors to fibrosis and BM remodeling, was increased in Stage II patients, and was greatest in Stage IV patients. Vascular pathology of the legs of PAD patients extends beyond atherosclerotic main inflow arteries and affects the entire vascular tree-including the smallest micro-vessels.

SUBMITTER: Mietus CJ

PROVIDER: S-EPMC7464726 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Abnormal Microvascular Architecture, Fibrosis, and Pericyte Characteristics in the Calf Muscle of Peripheral Artery Disease Patients with Claudication and Critical Limb Ischemia.

Mietus Constance J CJ Lackner Timothy J TJ Karvelis Petros S PS Willcockson Gregory T GT Shields Christina M CM Lambert Nicholas G NG Koutakis Panagiotis P Fuglestad Matthew A MA Hernandez Hernan H Haynatzki Gleb R GR Kim Julian K S JKS DeSpiegelaere Holly K HK Pipinos Iraklis I II Casale George P GP

Journal of clinical medicine 20200808 8

Work from our laboratory documents pathological events, including myofiber oxidative damage and degeneration, myofibrosis, micro-vessel (diameter = 50-150 μm) remodeling, and collagenous investment of terminal micro-vessels (diameter ≤ 15 µm) in the calf muscle of patients with Peripheral Artery Disease (PAD). In this study, we evaluate the hypothesis that the vascular pathology associated with the legs of PAD patients encompasses pathologic changes to the smallest micro-vessels in calf muscle. ...[more]

PMID: 32784470

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Project description: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.

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:Purpose: To investigate the outcomes of orbital atherectomy (OA) for the treatment of patients with peripheral artery disease (PAD) manifesting as claudication or chronic limb-threatening ischemia (CLTI). Materials and Methods: The database from the LIBERTY study (ClinicalTrials.gov identifier NCT01855412) was interrogated to identify 503 PAD patients treated with any commercially available endovascular devices and adjunctive OA for 617 femoropopliteal and/or infrapopliteal lesions. Cox regression analyses were employed to examine the association between baseline Rutherford category (RC) stratified as RC 2-3 (n=214), RC 4-5 (n=233), or RC 6 (n=56) and all-cause mortality, target vessel revascularization (TVR), major amputation, major adverse event (MAE), and major amputation/death at up to 3 years of follow-up. The mean lesion lengths were 78.7±73.7, 131.4±119.0, and 95.2±83.9 mm, respectively, for the 3 groups. Results: After OA, balloon angioplasty was used in >98% of cases, with bailout stenting necessary in 2.0%, 2.8%, and 0% of the RC groups, respectively. A small proportion (10.8%) of patients developed angiographic complications, without differences based on presentation. During the 3-year follow-up, claudicants were at lower risk for MAE, death, and major amputation/death than patients with CLTI. The 3-year Kaplan-Meier survival estimates were 84.6% for the RC 2-3 group, 76.2% for the RC 4-5 group, and 63.7% for the RC 6 group. The 3-year freedom from major amputation was estimated as 100%, 95.3%, and 88.6%, respectively. Among CLTI patients only, the RC at baseline was correlated with the combined outcome of major amputation/death, whereas RC classification did not affect TVR, MAE, major amputation, or death rates. Conclusion: Peripheral artery angioplasty with adjunctive OA in patients with CLTI or claudication is safe and associated with low major amputation rates after 3 years of follow-up. These results demonstrate the utility of OA for patients across the spectrum of PAD.

Dataset Information

Abnormal Microvascular Architecture, Fibrosis, and Pericyte Characteristics in the Calf Muscle of Peripheral Artery Disease Patients with Claudication and Critical Limb Ischemia.

Publications

Abnormal Microvascular Architecture, Fibrosis, and Pericyte Characteristics in the Calf Muscle of Peripheral Artery Disease Patients with Claudication and Critical Limb Ischemia.

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