Simultaneous Assessment of Coronary Microvascular Dysfunction and Ischemia With Non-obstructed Coronary Arteries With Intracoronary Electrocardiogram and Intracoronary Doppler

Coronary Microvascular Dysfunction has been consistently shown to play a considerable role in pathophysiology of Ischaemia with non-obstructed coronary arteries (INOCA). While the both diagnoses are individually related to remarkably worse outcome, there is no available method to simultaneously determine INOCA-CMD endotypes in vessel level, during the invasive diagnosis.

The investigators hereby hypothesize that, combined intracoronary electrocardiogram (IC-ECG) (considering the high sensitivity and specificity of IC-ECG for studied vessel-territory) and intracoronary doppler can simultaneously and successfully identify vessel specific coronary microvascular dysfunction and resulting ischemia, which may potentially enable immediate diagnosis and endotyping of CMD-INOCA subgroups during the invasive assessment of first ANOCA episode, obviating the need for further ischemia-studies such es SPECT, which have considerably higher costs and lower sensitivity.

Major coronary arteries of patients aged between 18 - 75 without obstructing coronary artery disease who have previously documented ischemia with non-obstructed coronary arteries (INOCA) via coronary angiogram and myocardial perfusion scan will be evaluated simultaneously with IC-ECG and intracoronary Doppler during rest and under adenosine induced hyperaemia.

Performance of the combined system to identify Coronary Microvascular Dysfunction with structural and functional subgroups as defined by abnormal Coronary Flow Reserve (CFR) and Hyperemic Microvascular Resistance (HMR) and Ischemia in downstream territories of same vessel area (as defined by perfusion scan) is intended to be determined.

The investigators also intend to interrogate the possible relationship between dynamic changes in IC-ECG parameters and invasively obtained intracoronary hemodynamic data.

Study Overview

• Status: Completed
• Conditions: Ischemic Heart Disease; Coronary Microvascular Disease; Microvascular Angina; Coronary Microvascular Dysfunction; Non-Obstructive Coronary Atherosclerosis; Microvascular Coronary Artery Disease

Detailed Description

Background and Rationale of Study

Coronary Microvascular Dysfunction has been consistently shown to play a considerable role in pathophysiology of Ischaemia with non-obstructed coronary arteries (INOCA). While the both diagnoses are individually related to remarkably worse outcome, there is no available method to simultaneously determine INOCA-CMD endotypes in vessel level, during the invasive diagnosis.

Hypothesis

The investigators hereby hypothesize that, combined intracoronary electrocardiogram (IC-ECG) (considering its high sensitivity for ischemia and specificity for studied vessel-territory) and intracoronary doppler can simultaneously and successfully identify vessel specific coronary microvascular dysfunction and resulting ischemia, which may potentially enable immediate diagnosis and endotyping of CMD-INOCA subgroups during the invasive assessment of first ANOCA episode, obviating the need for further ischemia-studies such as SPECT, which have considerably higher costs and lower sensitivity and requires more hospital visits.

Study Method

Major coronary arteries of patients aged between 18 - 75 without obstructing coronary artery disease who have previously documented ischaemia with non-obstructed coronary arteries (INOCA) via coronary angiogram and myocardial perfusion scan will be evaluated simultaneously with IC-ECG and intracoronary Doppler during rest and under adenosine induced hyperaemia after obtaining informed consent. Flow (APVr, APVh) data will be collected via intracoronary doppler during rest and adenosine induced hyperaemia in concordance with guidelines and Coronary Flow Reserve will be determined. Microvascular resistances (HMR, BMR) will be calculated with distal pressures and flow data.

Simultaneous with intracoronary Doppler, IC-ECG records will be obtained during rest and hyperaemia. Paper records will be digitized offline in MATLAB environment. Delta ST, Delta ST integral, Delta T, Delta T integral will be measured and calculated and quantified as continuous values.

All participants will be go through careful medical evaluation and presence of exclusion criteria will be assessed.

At the end of the data collection period, all available major coronary arteries are expected to have:

1. Myocardial Perfusion Scan result: whether they relate to (supply blood) ischemic territory.

2. Structural/Functional Microvascular Status: (CFR and HMR)

   -Definition of Coronary Microvascular Dysfunction and Subgroups: CMD is defined as CFR < 2.5. Those with concomitant HMR > 1.9 will be further labeled as structural CMD whereas vessels with CFR <2.5 and HMR <1.9 will be labeled as functional CMD.

3. IC-ECG parameters

• Study Type: Observational
• Enrollment (Actual): 35

Contacts and Locations

• Study Contact: Name: Murat Sezer, Professor, MD; Phone Number: +90 533 237 93 43; Email: sezermr@gmail.com

Study Locations

• Turkey
  • Istanbul, Turkey, 34290
    • Istanbul University, Istanbul Faculty of Medicine, Department of Cardiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

18 - 75 years old patients with previously documented ischemia with non-obstructed coronary arteries and positive ischemia test (myocardial perfusion scan or slow-flow) to be enrolled. Patients meeting at least one exclusion criteria won't be enrolled.

Description

Inclusion Criteria:

• ≥1 previous episode of typical angina pectoris with normal coronary angiograms (Angina with Non-obstructed Coronary Arteries)
• positive myocardial perfusion scan (MPS) for ischemia or slow-flow.

Exclusion Criteria:

• obstructive epicardial coronary artery disease of at least 1 coronary artery in angiogram
• lung disease causing severe bronchospasm
• NYHA III - IV Heart Failure
• Bundle Branch Block
• Hb < 10 g/dL
• Active Malignancy
• Active Infection
• Morbid Obesity
• Pacemaker (Actively Pacing)
• Peripheral Artery Disease
• Previous CABG
• Chronic Hypoxia due to lung diseases

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hyperemic Microvascular Resistance (HMR)	the ratio of mean distal coronary pressure to average flow velocity	Intraprocedural during coronary angiography
Coronary Flow Reserve (CFR)	the ratio between coronary blood flow at maximal hyperemia and at baseline condition	Intraprocedural during coronary angiography
Delta ST	absolute shift of ST segment in IC-ECG record (at J point)	Intraprocedural during coronary angiography
Delta ST Integral	absolute change in area between ST segment and isoelectric line	Intraprocedural during coronary angiography

Secondary Outcome Measures

Outcome Measure	Time Frame
Resting Average Peak Velocity	Intraprocedural during coronary angiography
Hyperemic Average Peak Velocity	Intraprocedural during coronary angiography

Other Outcome Measures

Outcome Measure	Time Frame
Basal Microvascular Resistance (BMR)	Intraprocedural during coronary angiography

Collaborators and Investigators

• Sponsor: Istanbul University

Publications and helpful links

General Publications

• Kunadian V, Chieffo A, Camici PG, Berry C, Escaned J, Maas AHEM, Prescott E, Karam N, Appelman Y, Fraccaro C, Louise Buchanan G, Manzo-Silberman S, Al-Lamee R, Regar E, Lansky A, Abbott JD, Badimon L, Duncker DJ, Mehran R, Capodanno D, Baumbach A. An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group. Eur Heart J. 2020 Oct 1;41(37):3504-3520. doi: 10.1093/eurheartj/ehaa503.
• Bigler MR, Seiler C. Detection of myocardial ischemia by intracoronary ECG using convolutional neural networks. PLoS One. 2021 Jun 14;16(6):e0253200. doi: 10.1371/journal.pone.0253200. eCollection 2021.
• Jansen TPJ, Konst RE, Elias-Smale SE, van den Oord SC, Ong P, de Vos AMJ, van de Hoef TP, Paradies V, Smits PC, van Royen N, Damman P. Assessing Microvascular Dysfunction in Angina With Unobstructed Coronary Arteries: JACC Review Topic of the Week. J Am Coll Cardiol. 2021 Oct 5;78(14):1471-1479. doi: 10.1016/j.jacc.2021.08.028.
• Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U, Kaski JC, Bairey Merz CN; Coronary Vasomotion Disorders International Study Group (COVADIS). International standardization of diagnostic criteria for microvascular angina. Int J Cardiol. 2018 Jan 1;250:16-20. doi: 10.1016/j.ijcard.2017.08.068. Epub 2017 Sep 8.

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2022
• Primary Completion (Actual): September 20, 2022
• Study Completion (Actual): October 15, 2022

Study Registration Dates

• First Submitted: July 19, 2022
• First Submitted That Met QC Criteria: July 20, 2022
• First Posted (Actual): July 25, 2022

Study Record Updates

• Last Update Posted (Actual): March 21, 2023
• Last Update Submitted That Met QC Criteria: March 18, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: INOCA; ANOCA; CMD; Coronary Microvascular Dysfunction; Ischemia with non-obstructive coronary arteries; Coronary Microvascular Disease; Microvascular Angina
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Angina Pectoris; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Ischemia; Atherosclerosis; Microvascular Angina
• Other Study ID Numbers: 2019/1285

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