Acute Local Metabolomic Alterations in Blood and Muscle Tissue in Intermittent Claudication

Study Overview
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Brief Summary
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The most common clinical presentation of lower extremity arterial disease is intermittent claudication. Current understanding of the pathophysiology of intermittent claudication, as well as its treatment options are limited. The progression of the disease may lead to lower limb amputation, which is devastating for patients' quality of life and is a huge socio-economic burden to society. Current study allows to determine the acute local metabolomic alterations in the ischaemic limb of the patient with intermittent claudication, and investigate the associations between the metabolomic alterations and the patient's maximal walking distance. This provides potentially valuable insight into the pathophysiology of this disease, and helps lay the groundwork for identifying potential novel targets for instituting more effective therapies for this high-risk population.

Official Title
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Acute Local Metabolomic Alterations in Blood and Muscle Tissue in Intermittent Claudication

Conditions
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Peripheral Arterial Occlusive Disease Fontaine Stage IIa

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: LEAD group: Patients with diagnosis of lower extremity arterial disease (Fontaine IIa). Control group: Healthy volunteers with no leg symptoms and an ankle-brachial index (ABI) of 1.0-1.4. Exclusion Criteria: Fontaine stages I or IIb-IV Exacerbation of limb ischaemia within the preceding 2 weeks; strong rest pain of any cause; age <18 or >80 years; fasting < 6 hours; time since last use of tobacco products < 6 hours; body mass index ≥ 35 kg/m2 poor sonographic visibility of femoral artery; angina; cardiac arrhythmia at the time of presentation; presence of cardiac pacemaker; myocardial infarction within the preceding 3 months; stroke within the preceding 6 months; ongoing anticoagulant therapy; ongoing dual antiplatelet therapy; any revascularization within the preceding 3 month; marked heart failure (NYHA III-IV); blood pressure ≥ 180/110 mmHg; blood pressure <100/70 mmHg; clinically significant heart valve disease; acute infectious disease; active malignancy or chemotherapy or disease-free < 5 years; type I diabetes or insulin therapy; other clinically significant and untreated endocrine disorders; moderate to severe bronchial asthma (GINA 2016); severe chronic obstructive pulmonary disease (mMRC grade 3-4); acute (KDIGO 2012) or chronic renal disease (eGFR-EPI <30mL/min/1.73 m2); acute or chronic liver disease; anemia (<110 g/L); neuroinflammatory or neurodegenerative disease; active rheumatism; other diseases and factors that markedly hinder the subject's ability to walk during the treadmill exercise. For control group exclusively: history of lower extremity arterial disease / ABI <1.0 or >1.4.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| LEAD (Fontaine IIa)<br>Patients with mild intermittent claudication. | |
| Control<br>Healthy controls. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in local metabolomic profile after treadmill exercise as reflected by arteriovenous gradients of low-molecular metabolites. | Measured using liquid chromatography combined with mass spectrometry (AbsoluteIDQ MxP Quant 500 Kit, BIOCRATES Life Sciences AG, Austria). | Blood sampling at two points in time: Baseline (Day 1) & 10-15 minutes after treadmill test (Day 2). | 
| Change in local inflammatory profile after treadmill exercise as reflected by arteriovenous gradients of inflammatory mediators (IL-6, MPO, SOD, NOX isoform 1, NOX isoform 2, NOX isoform 5, nitrotyrosine, 8-iso-PGF2α). | Measured using enzyme linked immunosorbent assay. Measurement unit: ng/mL. | Blood sampling at two points in time: Baseline (Day 1) & 10-15 minutes after treadmill test (Day 2). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in local metabolomic profile after treadmill exercise as reflected by absolute concentrations of low-molecular metabolites in muscle biopsy. | Measured using liquid chromatography combined with mass spectrometry (AbsoluteIDQ MxP Quant 500 Kit, BIOCRATES Life Sciences AG, Austria). | Biopsy at two points in time: Baseline (Day 1) & 15-20 minutes after treadmill test (Day 2). | 
| Correlations between maximal walking distance and exercise-induced changes in local metabolomic and inflammatory profiles. |  | Data analysis after the enrollment period. | 
| Correlations between baseline arterial functionality/hemodynamic parameters and exercise-induced changes in local metabolomic and inflammatory profiles. |  | Data analysis after the enrollment period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lower extremity arterial disease, peripheral artery disease, intermittent claudication, metabolism, metabolomics, arteriovenous gradients, biomarkers, inflammation, ischemia-reperfusion injury, local