Mechanisms Behind Microvascular Dysfunction in INOCA (ExINOCA-P1)

Identification of Mechanisms Behind Microvascular Dysfunction in Ischemia With No Obstructive Coronary Artery Disease

The purpose of the study is to identify the causes of chest pain in patients experiencing chest pain with no signs of narrowing in the coronary arteries of the heart.

Study Overview

• Status: Not yet recruiting
• Conditions: Coronary Microvascular Dysfunction; Ischaemia With Non Obstructed Coronary Arteries
• Intervention / Treatment: Diagnostic test: [15O]H2O-PET Imaging

Detailed Description

A significant number of patients with ischemic heart disease do not exhibit coronary obstruction, leading to their symptoms being attributed to coronary microvascular dysfunction, a condition known as ischemia with no obstructive coronary artery disease (INOCA). Despite a considerable patient population affected by INOCA, the specific mechanisms underlying this microvascular dysfunction are not fully understood, often resulting in a lack of targeted treatment. There is evidence to suggest that exercise capacity is linked to coronary microvascular function, an area yet to be explored.

This study aims to identify mechanisms underlying Coronary microvascular dysfunction (CMD) in angina and to assess whether exercise training can improve the condition. In study part I 30 patients with impaired coronary microvascular function and 30 asymptomatic controls will be studied to identify vascular and related molecular mechanisms underlying INOCA by investigating microvascular function in the heart and in cutaneous tissue, skeletal muscle, and adipose tissue.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Eva Prescott, MD, DMSc; Phone Number: 22572614; Email: Eva.Irene.Bossano.Prescott@regionh.dk
• Study Contact Backup: Name: Mads Fischer, Ph.D.; Phone Number: 24485450; Email: mf@nexs.ku.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Frederiksberg Hospital, Dept. of Cardiology, Building 16, Y3, Nordre Fasanvej 57, Frederiksberg, Denmark, 2000

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Ischemia with no obstruction of coronary arteries (INOCA) is estimated to affect >150.000 Danes and the majority are females. These patients have a shorter life expectancy than age matched controls and a higher incidence of major cardiovascular events (1,2).

INOCA is caused by microvascular dysfunction. When there is dysfunction in the microvascu-lature, the blood flow within the coronary vessels fails to increase adequately to meet the de-mand, resulting in ischemia and pain (angina).

Description

Inclusion Criteria:

Only for angina patients: Have CMD, defined as myocardial bloodflow re-serve (MBFR) < 2.5 or hyperemic myocardial blood flow (hMBF) < 2.3ml/g/min

Exclusion Criteria:

• Females of childbearing potential (defined as a premeno-pausal female capable of becoming pregnant). The female patient must either be postmenopausal, defined as amen-orrhea for at least 1 year, or surgically sterile
• Heart failure, defined as left ventricular ejection fraction of less than 40%
• Uncontrolled hypertension defined as blood pressure above target 140/90 for all
• Co-morbidity resulting in <1 year expected survival
• Considered by the investigator, for any reason, to be an unsuitable candidate for the study.
• Unable or unwilling to exercise, e.g. due to arthritis or injury*
• Already are regularly physically active and/or have a maximal oxygen uptake >45 ml/kg/min
• The subject has a known allergy to either: norepinephrine, adenosine, ketorolac, and or ascorbic acid (vitamin C).

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Ischemia and no obstructive coronary arteries; patients with angina and reduced myocardial blood flow reserve	Diagnostic test: [15O]H2O-PET Imaging; This imaging technique will be used to measure myocardial blood flow (MBF) and myocardial blood flow reserve (MBFR) in patients. The PET-CT scan involves the use of the radioactive tracer [15O]H2O to visualize blood flow in the heart, providing crucial data on coronary microvascular function.
Control; controls without angina	Diagnostic test: [15O]H2O-PET Imaging; This imaging technique will be used to measure myocardial blood flow (MBF) and myocardial blood flow reserve (MBFR) in patients. The PET-CT scan involves the use of the radioactive tracer [15O]H2O to visualize blood flow in the heart, providing crucial data on coronary microvascular function.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vascular function in response to acetylcholine stress	Vascular conductance measured by ultrasound doppler during infusion of acetylcholine	Baseline only

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vascular function in response to acetylcholine adenosine stress	Vascular conductance measured by ultrasound doppler during infusion of Adenosine	Baseline only
Myocardial Blood flow reserve	Determined by the clinical assessment of [15O]H2O-PET	Baseline only
Skeletal Muscle Microvascular Function	Evaluated by brachial artery ultrasound Doppler in response to exercise stress to measure blood flow responsiveness in skeletal muscles.	Baseline only
Changes in isolated small artery reactivity assessed with myography	Analyzed using myograph to study the tone of smooth muscle cells	Baseline only
Arterial Compliance	Determined by calculations made from intra-arterial pressure and arterial diameter measurements obtained via ultrasound Doppler to assess arterial compliance.	Baseline only
Plasma Lipids	Conducted through clinical chemical analysis to measure levels of HDL, and triglycerides in the blood, providing insights into lipid profiles.	Baseline only
Plasma HbA1c	Conducted through clinical chemical analysis to measure levels of HbA1c in the blood, providing insights into glucose metabolism.	Baseline only
Plasma Levels of Markers Related to Vascular Function	Assessed using Mesoscale/ELISA to quantify biomarkers associated with vascular function	Baseline only
Plasma Levels of Inflammatory Markers	Measured using Mesoscale/ELISA/O-Link platforms to evaluate the presence and levels of inflammatory markers	Baseline only
Arterial Blood Pressure	Monitored with automated blood pressure measurements at rest and during exercise to assess overall cardiovascular health and response to physical activity.	Baseline only
Cardiac Function	Changes in stroke volume using echocardiography during rest and exercise stress	Baseline only

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tone of smooth muscle cells	Changes in isolated small artery reactivity assessed with myography	Baseline only
Proteomic and transcriptomic analyses	Changes in gene and protein expressions patterns in small arteries	Baseline only

Collaborators and Investigators

• Sponsor: Bispebjerg Hospital
• Collaborators: University of Copenhagen
• Investigators: Study Chair: Ylva Hellsten, Professor, Department of Nutrition, Exercise and sports, University of Copenhagen

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): October 30, 2027
• Study Completion (Estimated): May 15, 2028

Study Registration Dates

• First Submitted: July 8, 2024
• First Submitted That Met QC Criteria: July 29, 2024
• First Posted (Actual): July 31, 2024

Study Record Updates

• Last Update Posted (Actual): July 31, 2024
• Last Update Submitted That Met QC Criteria: July 29, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia
• Other Study ID Numbers: ExINOCA - Part I

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No