Women's Ischemia Syndrome Evaluation (WISE) Pre-HFpEF

Women's Ischemia Syndrome Evaluation (WISE) Mechanisms of Coronary Microvascular Dysfunction Leading to Pre-Heart Failure With Preserved Ejection Fraction (HFpEF)

The purpose of this study is to examine small vessel disease (a condition in which the small arteries in the heart become narrowed). The investigators want to know how the small vessel disease contributes to pre-HFpEF (a condition with inadequate heart muscle function in the setting of preserved muscle pumping) and to better identify potential treatment for prevention of HFpEF. The main procedures of this study include up to 2 clinic visits (initial visit and a second clinical visit only if participants are unable to complete all research procedures at the initial visit); a 6-week phone interview visit, 4 quarterly follow-up phone interview visits in year 1; year 1 follow up cardiac MRI based on availability and ongoing annual follow-up phone interview visits to track progress. If participants choose to take part in this study, participants direct participation will end after 1 year, participants will then have the option of participating in ongoing annual check-in calls. Participants will be asked to undergo a physical exam and provide a completed medical history; complete a Cardiovascular (or Cardiac) Magnetic Resonance Imaging (CMRI) with contrast agent; complete questionnaires to describe heart symptoms and overall quality of life status; undergo blood draws to provide blood samples for research testing, and allow the study team to have access to medical records.

Study Overview

• Status: Recruiting
• Conditions: Coronary Microvascular Dysfunction; Heart Failure With Preserved Ejection Fraction (HFpEF)

Detailed Description

Coronary microvascular dysfunction (CMD) due to changes in the function and structure of coronary microcirculation in the absence of obstructive coronary artery disease (CAD) is poorly understood. Ischemia with no obstructive CAD (INOCA) and myocardial infarction with no obstructive CAD (MINOCA) are increasingly observed in women and men.

Once established, the investigators will be well positioned to aggressively target identified mechanistic targets in a specific well-characterized at-risk population, with the primary goal of preventing progression to HFpEF.

To address this novel hypothesis, the investigators propose the following Specific Aims:

Aim 1: Test the hypothesis that CMD-related ischemia contributes to myocellular damage and impaired ventricular relaxation. CMD will be measured directly, using our established intracoronary pharmacological vasoactive protocol, in subjects with signs/symptoms of ischemia but no obstructive CAD. In our labs (>420 patients), ~60% of those tested have evidence for CMD. All subjects will perform provocative stress testing with isometric handgrip - chosen for its unique ability to increase myocardial afterload and myocardial oxygen demand - while myocardial ischemia will be assessed directly through invasive simultaneous arterial and coronary sinus/great cardiac vein oxygen tension and lactate measurements, and continuous ECG's recordings. Left ventricular function will be directly assessed using Millar-catheter LV pressure-volume loops (perfected in our lab over the past 24 months). Stress-induced myocellular damage will be directly measured by coronary sinus/great cardiac vein hs-cTnI.

Aim 2: Test the hypothesis that CMD-related ischemic myocellular damage contributes to LV diastolic dysfunction progression. Subjects from Aim 1 will also undergo comprehensive cardiac magnetic resonance imaging (CMRI) at enrollment and 1-2 years later. The investigators will evaluate CMRI LV perfusion, myocardial scar, diffuse fibrosis, LV remodeling, and diastolic function. The investigatorswill leverage the strengths and resources of our world-renowned proteomics core to establish evidence of chronic myocellular damage using prospectively repeated ambulatory hs-cTnI determinations.

• Study Type: Observational
• Enrollment (Estimated): 180

Contacts and Locations

• Study Contact: Name: Nicole Tovar; Phone Number: 310-248-6960; Email: nicole.tovar@cshs.org
• Study Contact Backup: Name: Lorena Guzman; Phone Number: 3102486960; Email: lorena.guzman@cshs.org

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Recruiting
      • Cedars-Sinai Medical Center
      • Contact: C. Noel Bairey Merz, MD; Phone Number: 310-248-6960; Email: noel.baireymerz@cshs.org
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • University of Florida
      • Contact: Eileen Handberg, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Men and women undergoing invasive coronary angiography for suspected ischemia with no obstructive CAD, defined as ≥ 50% luminal diameter stenosis in ≥ 1 epicardial coronary artery.

Description

Inclusion:

1. 180 symptomatic men and women undergoing invasive coronary angiography for suspected ischemia with no obstructive CAD, defined as ≥50% luminal diameter stenosis in ≥1 epicardial coronary artery.
2. Preserved left ventricular ejection fraction (EF) ≥45%
3. Be > 18 years old
4. Be able to meet the requirement for a cardiac MRI, which means no metal devices in your chest, no claustrophobia and no angioedema
5. Be competent to give informed consent

Exclusion:

1. Subjects with severe or chronic kidney disease (CKD) with GFR<405 or acute kidney injury
2. Subjects with allergy to animal dander will be excluded since imaging will be done in BIRI (BIRI scanners are also used to image animals).
3. Subjects who have had four or more prior previous gadolinium contrast scans
4. Allergy/ hypersensitivity to adenosine, gadolinium, aminophylline or regadenoson
5. Second- or third-degree A-V block
6. Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker)
7. Subjects with mild to severe asthma

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CMR imaging	Change from Baseline at 1 year follow up will be assessed.	Baseline, Annual follow up
Rest-stress Millar pressure-volume measurement	LV diastolic function will be measured using LV end-diastolic pressure, minimal rate of LV pressure change (dP/dtmin).	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Questionnaire	Symptom History Questionnaire. Change from Baseline at each visit will be measure. There is no scale ranges for this questionnaire. This questionnaire results in raw data that is not calculated into a score or scale.	Baseline, 6 week, quarterly(year 1) and annual follow up
Questionnaire WISE Symptoms History	Detailed information on chest pain symptoms will include the WISE female angina questionnaire. Change from Baseline at each visit will be measure. There is no scale ranges for this questionnaire. This questionnaire results in raw data that is not calculated into a score or scale.	Baseline, quarterly(year 1) and annual follow up
SEATTLE ANGINA QUESTIONNAIRE	The SAQ quantifies patients' physical limitations caused by angina, the frequency of and recent changes in their symptoms, their satisfaction with treatment, and the degree to which they perceive their disease to affect their quality of life. Each scale is transformed to a score of 0 to 100. A higher score means better control of chest pain, chest tightness, angina, or shortness of breath. Change from Baseline at each visits will be measure.	Baseline, 6 week and annual follow up
Duke Activity Status Inventory (DASI)	It is a self-administered questionnaire that measures a patient's functional capacity. Change from Baseline at each visit will be measure. Maximum response is a total of 16.7 while minimum is 0.	Baseline, 6 week and annual follow up

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: University of Florida
• Investigators: Principal Investigator: C. Noel Bairey Merz, MD, FACC, Cedars-Sinai Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2019
• Primary Completion (Estimated): February 28, 2025
• Study Completion (Estimated): February 28, 2025

Study Registration Dates

• First Submitted: February 22, 2019
• First Submitted That Met QC Criteria: March 13, 2019
• First Posted (Actual): March 15, 2019

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Coronary angiography; Magnetic resonance imaging (MRI); Coronary Microvascular Dysfunction (CMD); Coronary Vascular Dysfunction (CVD)
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Heart Failure; Ischemia
• Other Study ID Numbers: 54999

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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