Women's Ischemia Syndrome Evaluation (WISE) Coronary Vascular Dysfunction

This research study is designed to investigate the approaches to noninvasive detection and assessment of coronary vascular dysfunction in women by comparing the testing results from the invasive standard care diagnostic procedure Angiogram and from the additional noninvasive diagnostic procedure CMR Imaging. The investigators want to specifically study 375 female patients who have signs or symptoms suggestive of heart disease but don't have obstructive coronary artery disease. Two study sites (Cedars-Sinai Medical Center and University of Florida) are recruiting participants.

The standard of care procedures include demographics, review of recent clinical symptoms, review of medications being taken, a physical exam, pre-angiogram blood collection, chest x-ray, ECG and heart angiogram. The research procedures for this study are the cold pressor testing, blood/urine collection, health questionnaire, the post-angiogram ECG and cardiac MRI.

Patients will be asked to undergo heart angiogram testing to test for abnormalities in their heart arteries. If the heart angiogram shows that the patients do not have blockages in major heart arteries, then the patients will have coronary flow reserve measurement test (as part of the heart angiogram) to determine whether the patients have abnormally functioning of the small heart arteries. This test will be performed by infusing the three drugs: adenosine, acetylcholine and nitroglycerin. The three drugs are naturally occurring substances and have been used for routine heart angiograms.

Cardiac Magnetic Resonance (CMR) imaging may help us more easily and non-invasively detect abnormalities in the inner layer of the heart muscle resulting from the abnormal function of the heart arteries. All the 375 participants will undergo baseline CMR imaging test and a subgroup of 200 participants will undergo a second CMR imaging test at their at least 1-year followup visit.

Patients will be followed up using phone questionnaires at 6 weeks, 6 months for 5 years, and than annually for 20 years thereafter. Other procedures in this study include obtaining informed consent, review of demographics, physical examination, ECG, blood and urine tests, clinical symptoms, medications, questionnaires, etc. The core laboratories include Blood, Lipoprotein, Chemistry Core Lab, Reproductive Hormone Core Lab, Inflammatory Marker Core Lab, Oxidative Stress Core Lab, and Angiographic Core Lab. Additionally, GCRC at Cedars Sinai will process, store and ship samples as needed/required.

Study Overview

• Status: Active, not recruiting
• Conditions: Cardiovascular Disease
• Intervention / Treatment: Procedure: Cardiac MRI

Detailed Description

See Brief Summary above.

• Study Type: Observational
• Enrollment (Estimated): 433

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Barbra Streisand Women's Heart Center
  • Florida
    • Gainesville, Florida, United States, 32610-0277
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Women undergoing clinically-ordered coronary angiography for suspected ischemia will be recruited. See the inclusion and exclusion criteria for details.

Description

Inclusion Criteria:

1. Symptomatic angina or anginal equivalent;
2. Aged 18 years or older;
3. No obstructive CAD at coronary angiography (performed within the previous 24 months).
4. Competent to give informed consent.

Exclusion Criteria:

1. Obstructive CAD ≥ 50% luminal diameter stenosis in ≥ 1 epicardial coronary artery,
2. Acute coronary syndrome (defined by the ACC/AHA criteria, Braunwald 2000),
3. Primary valvular heart disease clearly indicating the need for valve repair or replacement;
4. Patients with concurrent cardiogenic shock or requiring inotropic or intra-aortic balloon support;
5. Prior or planned percutaneous coronary intervention or CABG,
6. Acute MI;
7. Prior non-cardiac illness with an estimated life expectancy < 4 years;
8. Unable to give informed consent;
9. Chest pain with a non-ischemic etiology (e.g.,pericarditis, pneumonia, esophageal spasm);
10. Contraindications to CMRI (e.g., AICD, pacemaker, untreatable claustrophobia or known angio-edema).
11. Contraindications to adenosine or Regadenoson (Lexiscan)
12. Women with intermediate coronary stenoses (> 20% but < 50% luminal diameter stenosis assessed visually at the time of angiography) will undergo clinically indicated IVUS testing based on the judgment of the operator; those determined to have flow-obstructing stenosis will be excluded from the overall study.
13. Participation in a research study that conflicts with the current WISE study.
14. Women with coronary stenosis ≥ 50% in any epicardial coronary artery, assessed visually at the time of angiography, will not be included in the CRT subgroup.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Abnormal cardiac magnetic resonance imaging (CMRI)	Subjects will be contacted at 6-week followup and then annually indefinitely.	30 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resource utilization and costs	Annual costs will include cardiovascular hospitalizations, coronary revascularizations and angiography, outpatient testing, and visits to generalists, specialists, nurse practitioners/ physician's assistants, or community clinics.	30 years
Persistent Chest Pain Symptoms	Detailed information on chest pain symptoms will include the traditional angina questionnaire and the WISE female angina questionnaire	30 years
Quality of Life Outcomes	Quality of life and functional capacity will be collected using the standard instruments of SAQ and DASI	30 years

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Pittsburgh; University of Florida
• Investigators: Principal Investigator: C. Noel Bairey Merz, MD, FACC, Cedars-Sinai Medical Center; Principal Investigator: Carl J Pepine, MD, MACC, University of Florida

Publications and helpful links

General Publications

• Jalnapurkar S, Landes S, Wei J, Mehta PK, Shufelt C, Minissian M, Pepine CJ, Handberg E, Cook-Wiens G, Sopko G, Bairey Merz CN. Coronary endothelial dysfunction appears to be a manifestation of a systemic process: A report from the Women's Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction (WISE-CVD) study. PLoS One. 2021 Sep 27;16(9):e0257184. doi: 10.1371/journal.pone.0257184. eCollection 2021.
• AlBadri A, Wei J, Quesada O, Mehta PK, Xiao Y, Ko YA, Anderson RD, Petersen J, Azarbal B, Samuels B, Henry TD, Cook-Wiens G, Handberg EM, Van Eyk J, Pepine CJ, Bairey Merz CN. Coronary Vascular Function and Cardiomyocyte Injury: A Report From the WISE-CVD. Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):3015-3021. doi: 10.1161/ATVBAHA.120.314260. Epub 2020 Oct 8.
• Wei J, Bakir M, Darounian N, Li Q, Landes S, Mehta PK, Shufelt CL, Handberg EM, Kelsey SF, Sopko G, Pepine CJ, Petersen JW, Berman DS, Thomson LEJ, Bairey Merz CN. Myocardial Scar Is Prevalent and Associated With Subclinical Myocardial Dysfunction in Women With Suspected Ischemia But No Obstructive Coronary Artery Disease: From the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Study. Circulation. 2018 Feb 20;137(8):874-876. doi: 10.1161/CIRCULATIONAHA.117.031999. No abstract available.
• Thomson LE, Wei J, Agarwal M, Haft-Baradaran A, Shufelt C, Mehta PK, Gill EB, Johnson BD, Kenkre T, Handberg EM, Li D, Sharif B, Berman DS, Petersen JW, Pepine CJ, Bairey Merz CN. Cardiac magnetic resonance myocardial perfusion reserve index is reduced in women with coronary microvascular dysfunction. A National Heart, Lung, and Blood Institute-sponsored study from the Women's Ischemia Syndrome Evaluation. Circ Cardiovasc Imaging. 2015 Apr;8(4):10.1161/CIRCIMAGING.114.002481 e002481. doi: 10.1161/CIRCIMAGING.114.002481.
• Wei J, Mehta PK, Johnson BD, Samuels B, Kar S, Anderson RD, Azarbal B, Petersen J, Sharaf B, Handberg E, Shufelt C, Kothawade K, Sopko G, Lerman A, Shaw L, Kelsey SF, Pepine CJ, Merz CN. Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. JACC Cardiovasc Interv. 2012 Jun;5(6):646-53. doi: 10.1016/j.jcin.2012.01.023.

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2008
• Primary Completion (Actual): September 15, 2015
• Study Completion (Estimated): August 31, 2051

Study Registration Dates

• First Submitted: January 28, 2009
• First Submitted That Met QC Criteria: January 29, 2009
• First Posted (Estimated): January 30, 2009

Study Record Updates

• Last Update Posted (Actual): July 20, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: MRI; Cardiac; Coronary Vascular Dysfunction
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Ischemia
• Other Study ID Numbers: IRB# 14906; 5R01HL090957 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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