Insulin Resistance and Coronary Microvascular Dysfunction in Patients with Myocardial Ischemia and Non-obstructive Coronary Artery Disease (IRIN)

The goal of this prospective study is to assess the correlation between coronary microvascular disfunction and insulin resistance in patients with INOCA.

Patients with ANOCA and without diabetes will undergo invasive coronary microvascular assessment through coronary angiography and insulin resistance assessment through hyperinsulinemic-euglycemic clamp test.

Patients enrolled in the study will be followed for a period of 2 years to monitor their clinical status.

Study Overview

• Status: Recruiting
• Conditions: Insulin Resistance; Coronary Microvascular Disease; Coronary Microvascular Dysfunction
• Intervention / Treatment: Diagnostic test: Thermodilution based assessment of coronary microcirculation; Diagnostic test: Hyperinsulinemic-euglycemic Clamp test

Detailed Description

This is a prospective, experimental, single-center, explorative study designed to assess the correlation between coronary microvascular disfunction and insulin resistance in patients with INOCA.

Patients identified as eligible for the protocol will be asked for written informed consent to participate in the study.

Participants will undergo multimodality diagnostic tests as per standard clinical practice and international recommendations:

1. Fasting glucose, fasting insulin, HOMA index, glycated haemoglobin and oral glucose tolerance test (OGTT) will be assessed to rule out diabetes.
2. Transthoracic echocardiography will be performed to evaluate cardiac function and cardiac remodeling.
3. Coronary angiography will be performed to rule out obstructive CAD defined as angiographic stenosis ≥ 70% of one or more main epicardial coronary arteries (defined as vessels with diameter >2.0 mm) and/or fractional flow reserve (FFR) ≤ 0,80 as indicated by the latest European Guidelines.
4. In case of angiographic evidence of unobstructive CAD, participants will undergo coronary microvascular function assessment using standard coronary pressure guidewire as indicated by the latest European Guidelines according to the recently described Fullphysiology method. If clinically indicated, in case of suspected epicardial or microvascular spasm, endothelial-dependent vasomotor function will be evaluated using a standard vasoreactivity test based on incremental doses of acetylcoline infusion as indicated by the latest European Guidelines.
5. Patients will undergo hyperinsulinemic-euglycemic clamp test at Diabetology Unit of AOUI Verona to evaluate insulin resistance and the metabolic risk. In patients with no clinical concerns, adequate pharmacological washout from betablockers, ace inhibitors, sartans and/or calcium antagonists will be considered before performing the clamp test.
6. Patients will undergo clinical follow up at 6 and 12 months via outpatient clinic or telephone contacts. Fasting glucose, fasting insulin, HOMA index and glycated haemoglobin will be re-assessed at 12 months.
7. Transthoracic echocardiography will be repeated at 12 months.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Natascia Antonioli; Phone Number: 0039 0458122320; Email: studi.clinici.cardiologia@aovr.veneto.it

Study Locations

• Italy
  • VR
    • Verona, VR, Italy, 37126
      • Recruiting
      • Azienda Ospedaliera Universitaria di Verona
      • Contact: Flavio Luciano Ribichini; Phone Number: 0039 0458122320; Email: flavio.ribichini@univr.it
      • Contact: Roberto Scarsini, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged over 18 years.
• Cardiac chest pain with evidence of myocardial ischemia at noninvasive myocardial stress imaging and clinical indication to diagnostic coronary angiography
• Willing and able to give informed consent for participation in the study

Exclusion Criteria:

• Obstructive CAD (defined as more than 70% luminal stenosis and/or FFR ≤0.80 in 1 or more epicardial vessels).
• History of previous myocardial infarction, percutaneous revascularization or coronary-aortic bypass graft (CABG) surgery.
• Diagnosis of type II diabetes.
• BMI ≥ 35 kg/m2.
• Stage IV and V of chronic kidney disease (eGFR ≤ 30 ml/min, estimated through CKD - EPI Creatinine Equation).
• Allergy or other contraindication to iodinated contrast and/or gadolinium and/or adenosine.
• Chronic resting O2 saturation ≤ 85%.
• Pregnancy or suspected pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Non-diabetic patients with ANOCA; Thermodilution based assessment of coronary microcirculation with the derivation of CFR and IMR; Hyperinsulinemic euglycemic clamp for insulin resistance assessment

Diagnostic test: Thermodilution based assessment of coronary microcirculation; Coronary microvascular assessment with the derivation of CFR, IMR and MRR will be performed using a standard pressure/thermodilution guidewire.; Diagnostic test: Hyperinsulinemic-euglycemic Clamp test; Infusion of insulin and glucose adjusting rate of glucose infusion to maintaine plasma glucose around 90 mg/dL by monitoring plasma glucose levels every 5-10 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between coronary microvascular dysfunction and insulin resistance	Correlation between the index of microcirculatory resistance (IMR) and the M-value evaluated with the hyperinsulinemic-euglycemic clamp test as a measure of insulin resistance	At baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation in vasomotor function in patients with and without IR	Difference in vasomotor dysfunction at vasoreactivity test with acetylcholine in patients with and without IR	At baseline
Adverse clinical events	Composite of cardiovascular death, new hospitalization for HF and/or ACS during follow-up	12 months

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Universitaria Integrata Verona
• Investigators: Principal Investigator: Roberto Scarsini MD PhD, Azienda Ospedaliera Universitaria di Verona

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2024
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: September 12, 2024
• First Submitted That Met QC Criteria: September 12, 2024
• First Posted (Estimated): September 19, 2024

Study Record Updates

• Last Update Posted (Estimated): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 12, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Insulin Resistance; INOCA; ANOCA; CMD; Coronary Microvascular Dysfunction; Coronary Microvascular Disease; hyperinsulinemic-euglycemic clamp test
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Hyperinsulinism; Angina Pectoris; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Ischemia; Insulin Resistance; Microvascular Angina
• Other Study ID Numbers: IRIN (225CET)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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