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

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.

Study Overview

• Status: Recruiting
• Conditions: Peripheral Arterial Occlusive Disease Fontaine Stage IIa

• Study Type: Observational
• Enrollment (Anticipated): 40

Contacts and Locations

Study Locations

• Estonia
  • Tartumaa
    • Tartu, Tartumaa, Estonia, 50406
      • Recruiting
      • Tartu University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with mild intermittent claudication (Fontaine IIa).

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
LEAD (Fontaine IIa); Patients with mild intermittent claudication.
Control; Healthy controls.

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal walking distance on a treadmill (m).		During treadmill test (Day 2).
Ankle-brachial index (no units).		Baseline (Day 1).
Femoral artery intima-media thickness (mm).		Baseline (Day 1).
Peripheral blood pressure, central blood pressure (mmHg).		Baseline (Day 1).
Aortic pulse wave velocity (m/s).		Baseline (Day 1).
Aortic augmentation index (%).		Baseline (Day 1).
Identification of systemic metabolomic profile as reflected by absolute concentrations of low-molecular metabolites in peripheral blood sample.	Measured using liquid chromatography combined with mass spectrometry (AbsoluteIDQ MxP Quant 500 Kit, BIOCRATES Life Sciences AG, Austria).	Blood sampling at one point in time: Baseline (Day 1)
Identification of systemic inflammatory profile as reflected by absolute concentrations of inflammatory mediators (IL-6, MPO, SOD, NOX isoform 1, NOX isoform 2, NOX isoform 5, nitrotyrosine, 8-iso-PGF2α) in peripheral blood sample.	Measured using enzyme linked immunosorbent assay. Measurement unit: ng/mL.	Blood sampling at one point in time: Baseline (Day 1)

Collaborators and Investigators

• Sponsor: University of Tartu
• Collaborators: Tartu University Hospital; Estonian Science Foundation
• Investigators: Study Chair: Kaido Paapstel, MD, PhD, University of Tartu; Study Chair: Kalle Kilk, MD, PhD, University of Tartu; Study Chair: Holger Post, MD, University of Tartu

Publications and helpful links

Helpful Links

• Endothelial Research Centre

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2022
• Primary Completion (Anticipated): August 1, 2023
• Study Completion (Anticipated): August 1, 2025

Study Registration Dates

• First Submitted: September 28, 2021
• First Submitted That Met QC Criteria: November 5, 2021
• First Posted (Actual): November 8, 2021

Study Record Updates

• Last Update Posted (Actual): May 25, 2022
• Last Update Submitted That Met QC Criteria: May 18, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: biomarkers; inflammation; metabolism; intermittent claudication; peripheral artery disease; lower extremity arterial disease; local; metabolomics; arteriovenous gradients; ischemia-reperfusion injury
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Intermittent Claudication; Arterial Occlusive Diseases
• Other Study ID Numbers: 350/T-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No