Impact of Exercise Training on Ischemia With Non-Obstructive Coronary Arteries (INOCA): The ExINOCA Study (ExINOCA)

Ischemia With No Obstruction of Coronary Arteries: Underlying Mechanisms and the Impact of Exercise Training (EXINOCA)

The purpose of the study is to identify causes of chest pain in patients experiencing chest pain with no signs of narrowing of the coronary arteries of the heart, and to investigate whether physical exercise can improve coronary microvascular function.

Hypotheses:

The first hypothesis is that in INOCA, with reduced function of microvasculature of the heart, this reduced function also occurs in other organs of the body.

The second hypothesis is that regular physical activity (aerobic exercise training) can improve coronary microvascular function, reduce symptoms, and that there is a parallel improvement in vascular function in other organs of the body.

Study Overview

• Status: Recruiting
• Conditions: Coronary Microvascular Disease; CMD
• Intervention / Treatment: Other: Exercise training

Detailed Description

A significant number of patients suspected of chronic coronary syndrome do not have coronary artery obstruction and in a large proportion of these, their symptoms are attributed to coronary microvascular dysfunction (CMD), a condition known as ischemia with no obstructive coronary artery disease (INOCA). Despite a considerable patient population affected by INOCA, the specific mechanisms underlying CMD 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, positing that exercise training could potentially reverse microvascular dysfunction and address its mechanistic origins, a hypothesis yet to be explored.

This study aims to identify mechanisms underlying CMD in angina and to assess whether exercise training can improve the condition.

The current study is a randomized controlled trial testing the effect of exercise training in patients with CMD. 100 patients will be randomized 1:1 to exercise training or control. The primary outcome is coronary microvascular function, secondary outcomes include symptoms and microvascular function in cutaneous tissue, skeletal muscle, and adipose tissue.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Eva Prescott, MD, DMSc; Phone Number: 004522572614; Email: Eva.Irene.Bossano.Prescott@regionh.dk
• Study Contact Backup: Name: Mads Fischer, MSc; Phone Number: +45 23 46 36 66; Email: mf@nexs.ku.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Not yet recruiting
    • Frederiksberg Hospital, Dept. of Cardiology, Building 16, Y3, Nordre Fasanvej 57, Frederiksberg, Denmark, 2000
    • Contact: Eva Prescott, MD, DMSc; Phone Number: +45 4026 2134; Email: Eva.Irene.Bossano.Prescott@regionh.dk
    • Contact: Mads Fischer, MSc; Phone Number: +4524485450; Email: mf@nexs.ku.dk
  • Frederiksberg, Denmark, 2000
    • Recruiting
    • Frederiksberg Hospital, Dept. of Cardiology, Building 16, Y3, Nordre Fasanvej 57
    • Contact: Eva Prescott, MD, DMSc; Phone Number: +45 4026 2134; Email: Eva.Irene.Bossano.Prescott@regionh.dk
    • Contact: Mads Fischer, MSc; Phone Number: +4524485450; Email: mf@nexs.ku.dk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Coronary microvascular dysfunction, defined as myocardial bloodflow reserve (MBFR) < 2.5 or hyperemic myocar-dial blood flow (hMBF)<2.3 ml/g/min using [15O]H2O-PET
• No obstructive coronary artery disease

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 un-suitable candidate for the study.
• Unable or unwilling to exercise, e.g. due to arthritis or in-jury*
• Already are regularly physically active and/or have a maxi-mal oxygen uptake >45 ml/kg/min

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Exercise; The exercise intervention consists of supervised training 40-50 minutes x 3 weekly for 12 weeks.	Other: Exercise training; The training sessions are consist of cycling and as follows: a 10 min warm-up at a light intensity, 20-35 min of cycling exercise in intervals at varying intensities from light (~60% of max heart rate) to more intensive (80-90% of max heart rate) and ending with 5 min of warm-down at a light intensity. The training intensity will be progressive during the course of the intervention period. The cycling training sessions are supervised . Home training is allowed up to once a week if participants are able to adhere to the prescribed intensity levels. Training sessions are closely monitored to ensure effectiveness and safety. This includes heart rate monitoring, perceived exertion assessment.; Other Names: Physical activity; Endurance training
No Intervention: Control; The participants who are randomized to the no-training group will be offered exercise train-ing after the intervention is completed. Participants will be encouraged to not change their lifestyle or medication throughout the study period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Myocardial Blood Flow Reserve (MBFR)	Change in MBFR assessed by [15O]H2O-PET-scan	From baseline and after 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in symptom burden assessed by Seattle Angina Questionnaire	Seattle angina questionnaire/selfreported (scale range 0-100, 0=poor and 100=excellent health status)	From baseline and after 3 months
Change in exercise capacity	Oxygen uptake during exhaustive exercise	From baseline and after 3 months
Change in global rest perfusion in patients with angina symptoms and CMD	Change in Myocardial Blood Flow assessed by [15O]H2O-PET-scan	From baseline and after 3 months
Change in global stress perfusion in patients with angina symptoms and CMD	Change in hyperemic Myocardial Blood Flow assessed by [15O]H2O-PET-scan	From baseline and after 3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vascular Function Adaptations	Changes in Arterial compliance (C = ΔV/ ΔP) calculated from intraarterial pressure ΔP and arterial diameter (ΔD) measured by ultrasound Doppler	From baseline and after 3 months
Changes in skin microvascular function	Hand microcirculatory blood flow assessed by Laser Speckle Contrast Imaging	From baseline and after 3 months
Change in plasma levels of markers related to vascular function	Plasma levels of markers related to vascular function assessed by Mesoscale/ELISA	From baseline and after 3 months
Changes in Arterial Blood Pressure	Assessed by automated blood pressure at rest	From baseline and after 3 months
Change in plasma Lipids	Conducted through clinical chemical analysis to measure levels of HDL, and triglycerides in the blood, providing insights into lipid profiles.	From baseline and after 3 months
Changes in Plasma Levels of Inflammatory Markers	Measured using Mesoscale/ELISA/O-Link platforms to evaluate the presence and levels of inflammatory markers, indicating systemic inflammation.	From baseline and after 3 months
Proteomic and transcriptomic analyses	Changes in gene and protein expressions patterns in small arteries	From baseline and after 3 months

Collaborators and Investigators

• Sponsor: Bispebjerg Hospital
• Collaborators: University of Copenhagen
• Investigators: Principal Investigator: Eva Prescott, MD, DMSc, Department of Nutrition, Exercise and sports, University of Copenhagen; Principal Investigator: Ylva Hellsten, Department of Nutrition, Exercise and sports, University of Copenhagen

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: July 4, 2024
• First Submitted That Met QC Criteria: July 29, 2024
• First Posted (Actual): July 31, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 20, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Myocardial Ischemia; Angina Pectoris; Ischemia; Microvascular Angina
• Other Study ID Numbers: ExINOCA

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