WISE CVD - Continuation (WISE HFpEF)

NCT02582021 | Recruiting

• 1 other identifier: Pro00037321
• Study Type: observational
• Target: 220
• Locations: 1 country
• Sites: 1

Brief Summary

The Women's Ischemia Study Evaluation (WISE), a cohort study of over 1000 women, has made many contributions to the understanding of cardiovascular disease. A milestone acknowledged in the 2011 AHA Herrick Lecture is the role of Coronary Microvascular Dysfunction (CMD) in women with symptoms/signs of ischemia without obstructive coronary artery disease (CAD). While in 1996, CMD was considered "an imaging artifact", in 2013, it is a widely accepted as a pathophysiologic process requiring systematic cohesive scientific pursuit. CMD is prevalent, associated with adverse clinical outcomes, poor quality of life and healthcare costs rivaling obstructive CAD. There are 2-3 million US women with CMD, and 100,000 new cases projected annually placing CMD prevalence, morbidity and costs higher than all female reproductive cancers combined. Among women with ischemia, preserved ejection fraction and no obstructive CAD, it has been observed that there are relatively more new onset heart failure (HF) hospitalizations than nonfatal myocardial infarction (MI). It has been hypothesized that CMD contributes to left ventricular (LV) diastolic dysfunction and subsequent heart failure with preserved ejection fraction (HFpEF). Preliminary data further suggests that left ventricular diastolic dysfunction is linked to CMD via a mechanism of augmentation and/or perpetuation by cardiomyocyte fat accumulation. HFpEF is prevalent in women and older men, but poorly understood. Mechanistic understanding is critical to HFpEF intervention and guideline development. The study hypotheses are as follows:

1. 1.Risk factor conditions (hypertension, dyslipidemia, dysglycemia, loss of estrogen) promote an inflammatory and pro-oxidative state making the microvasculature vulnerable;
2. 2.Vulnerable coronary microvasculature becomes dysregulated (sympathetic nervous system activation, endothelial dysfunction, changes in vascular smooth muscle activation, spasm) causing repeated episodes of transient ischemia;
3. 3.Repeated ischemia-reperfusion episodes facilitate preconditioning with preservation of cardiomyocyte contractile and microvascular function against ischemic injury;
4. 4.Ischemia-reperfusion and preconditioning lead to cardiomyocyte fat accumulation and relaxation impairment resulting in diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF).

Conditions

Microvascular Coronary Dysfunction; Cardiovascular Disease

Keywords

Microvascular Coronary Dysfunction (MCD); Magnetic resonance imaging (MRI); Coronary angiography; Coronary Vascular Dysfunction (CVD)

Outcome Measures

Primary Outcomes (1)

• Cardiovascular (CV) events

  up to 30 years

Secondary Outcomes (4)

• Persistent Chest Pain Symptoms: SAQ

  up to 30 years

• Persistent Chest Pain Symptoms: WISE female angina Questionnaire

  Up to 30 years

• Quality of Life Outcomes: SAQ

  up to 30 years

• Quality of Life Outcomes: DASI

  up to 30 years

Study Arms (2)

Women

Women undergoing clinically-ordered coronary angiography for signs and symptoms of ischemia who have no obstructive coronary artery disease (CAD)

Procedure: Coronary Angiography; Procedure: Coronary Reactivity Testing; Procedure: Cardiac Magnetic Resonance Imaging; Procedure: Cardiac Magnetic Resonance Angiography; Procedure: Rest-Stress Millar Testing; Procedure: Aortic vasorelaxation tests

Women or men

Women and men hospitalized for signs and symptoms of ischemia and evidence of Heart Failure with preserved ejection fraction (HFpEF) who have not undergone a clinically-ordered coronary angiography

Procedure: Cardiac Magnetic Resonance Imaging; Procedure: Cardiac Magnetic Resonance Angiography; Procedure: Computed Coronary Tomographic Angiography; Procedure: Rest-Stress Millar Testing; Procedure: Aortic vasorelaxation tests

Interventions

Coronary Angiography PROCEDURE

A coronary angiogram is a procedure that uses x-ray imaging to see the heart's blood vessels; it is a part of Heart (cardiac) catheterization procedure. During a coronary angiogram, a type of dye that's visible by an x-ray machine is injected into the blood vessels of the heart. The x-ray machine rapidly takes a series of images (angiograms). The Coronary Reactivity test (CRT), heart pressure (Millar) evaluation, and Millar stress testing are performed during the coronary angiography.

Women

Coronary Reactivity Testing PROCEDURE

An angiography procedure specifically designed to examine the blood vessels in the heart and how they respond to different medications.

Also known as: CRT

Women

Cardiac Magnetic Resonance Imaging PROCEDURE

Noninvasive high resolution imaging test; Optimized magnetic resonance imaging technique for use in the cardiovascular system - use of ECG gating and rapid imaging sequences. Handgrip, mild leg exercise, and brief Valsalva Maneuver will be conducted to characterize cardiac response to stress. The CMRA is performed as part of the CMRI.

Also known as: CMRI

Women; Women or men

Cardiac Magnetic Resonance Angiography PROCEDURE

Test for validation purposes against gold-standard Angiography. CMRA is a part of the CMRI test. The residual contrast (gadolinium) circulating in the blood stream (following the CMRI prior images) is sufficient for CMRA evaluation.

Also known as: CMRA

Women; Women or men

Computed Coronary Tomographic Angiography PROCEDURE

Noninvasive, imaging method that uses a computed tomography (CT) scanner to look at the structures and blood vessels of the heart.

Also known as: CCTA

Women or men

Rest-Stress Millar Testing PROCEDURE

Handgrip, mild leg exercise, and brief Valsalva Maneuver will be conducted to characterize cardiac response to stress. They are designed to test how your heart muscle is functioning. Rest-stress Millar testing is performed during the coronary angiography and Cardiac Magnetic Resonance Imaging.

Women; Women or men

Aortic vasorelaxation tests PROCEDURE

Non-invasive clinical test. Repeat blood pressure and heart rate per minute will be read for three times; Your pulse wave velocity, pulse wave analysis and central pressure measurements will be recorded.

Also known as: Aortic pulse wave velocity-Pulse wave analysis

Women; Women or men

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

A group of symptomatic women undergoing coronary angiography (n=120) for suspected ischemia and no obstructive CAD, defined as ≥50% luminal diameter stenosis in ≥1 epicardial artery, will be recruited. A group of women and men hospitalized for HFpEF, defined by the ESC criteria (n=100) who have not yet undergone coronary angiography will also be recruited for the study.

You may qualify if:

• For the new cohort n=120 women undergoing coronary angiography:
• Symptomatic angina or anginal equivalent
• Age ≥ 18
• Participant is willing to give written informed consent
• For the cohort n=100 women and men hospitalized for HFpEF (defined by ESC guidelines):
• Age ≥ 18
• Signs and symptoms of heart failure
• Preserved ejection fraction, left ventricular ejection fraction (LVEF) ≥45% prior to study entry.
• Structural evidence of cardiovascular abnormalities: elevated brain naturetic peptide, evidence of abnormal filling or relaxation, left ventricular hypertrophy, or an increased left atrial size
• Evidence of elevated filling pressures: LVEDP or PCWP at rest \> 15 mmHg and/or with exercise ≥25 mmHg, exercise E/e' \>13, elevated BNP, or use of diuretic
• Participant is willing to give written informed consent

You may not qualify if:

• For the new cohort n=120 women undergoing invasive coronary angiography:
• Obstructive CAD ≥ 50% luminal diameter stenosis in ≥ 1 epicardial coronary artery
• STEMI within 3-7 days post MI, or Acute coronary syndrome/NSTEMI with with symptoms or signs of acute myocardial ischemia within the last 12 to 24 hours prior to the research procedure, as outlined in ACC/AHA guidelines.
• Primary valvular heart disease clearly indicating the need for valve repair or replacement
• Patients with concurrent cardiogenic shock or requiring inotropic or intra-aortic balloon support or LVEF\<45%
• Prior or planned percutaneous coronary intervention or coronary artery bypass grafting for obstructive coronary atherosclerosis
• Non-cardiac illness with a life expectancy \< four years
• Unable to give informed consent
• Chest pain which has an alternative non-ischemic etiology, i.e. pericarditis, pulmonary embolism, pleurisy, pneumonia, esophageal spasm, etc.
• Contraindications to CMRI, such as internal cardiac defibrillator, untreatable claustrophobia or known angioedema
• Contraindications to adenosine or regadenoson including severe COPD and asthma
• End stage renal or liver disease
• Women with intermediate coronary stenoses (\>20% but \<50% luminal diameter stenosis assessed visually at the time of angiography) will undergo clinically indicated fractional flow reserve (FFR) based on the judgment of the operator; those determined to have flow-obstructing stenosis will be excluded.
• Documented allergy to gadolinium
• For the new cohort n=100 women and men hospitalized for HFpEF:

Sponsors & Collaborators

• Cedars-Sinai Medical Center: lead

Study Sites (1)

Cedars-Sinai Women's Heart Center

Los Angeles, California, 90048, United States

RECRUITING

Related Publications (4)

• Nelson MD, Gomez-Arnold JM, Wei J, Lauzon M, Zamani SK, Maughan J, Obrutu O, Shufelt C, Handberg E, Pepine C, Bairey Merz CN. Contributors to high left ventricular ejection fraction in women with ischemia and no obstructive coronary artery disease: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) Study. Am Heart J. 2024 Dec;278:41-47. doi: 10.1016/j.ahj.2024.08.021. Epub 2024 Sep 2.

  PMID: 39233211 DERIVED

• Ya'Qoub L, Elgendy IY, Pepine CJ. Non-obstructive Plaque and Treatment of INOCA: More to Be Learned. Curr Atheroscler Rep. 2022 Sep;24(9):681-687. doi: 10.1007/s11883-022-01044-4. Epub 2022 Jul 4.

  PMID: 35781776 DERIVED

• Quesada O, Hermel M, Suppogu N, Aldiwani H, Shufelt C, Mehta PK, Cook-Wiens G, Maughan J, Berman DS, Thomson LEJ, Handberg EM, Pepine CJ, Bairey Merz CN, Wei J. Temporal Trends in Angina, Myocardial Perfusion, and Left Ventricular Remodeling in Women With No Obstructive Coronary Artery Disease Over 1-Year Follow-Up: Results From WISE-CVD. J Am Heart Assoc. 2020 Jul 7;9(13):e016305. doi: 10.1161/JAHA.119.016305. Epub 2020 Jun 24.

  PMID: 32578481 DERIVED

• Joung S, Wei J, Nelson MD, Aldiwani H, Shufelt C, Tamarappoo B, Berman D, Thomson LEJ, Bairey Merz CN. Progression of coronary microvascular dysfunction to heart failure with preserved ejection fraction: a case report. J Med Case Rep. 2019 May 6;13(1):134. doi: 10.1186/s13256-019-2074-z.

  PMID: 31056078 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

A maximum of 45 mL of whole blood will be collected, which will be processed and stored as serum, plasma, and DNA for biomarkers and for genetic testing.

MeSH Terms

Conditions

Cardiovascular Diseases

Study Officials

• C. Noel Bairey Merz, MD, FACC

  Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

BSWHC Research, MS

CONTACT

310-423-9666; bswhc.research@cshs.org

Fatima Bataz, BS

CONTACT

310-248-7888; fatima.bataz@cshs.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director

Study Record Dates

• First Submitted: October 5, 2015
• First Posted: October 21, 2015
• Study Start: November 1, 2015
• Primary Completion (Estimated): February 1, 2030
• Study Completion (Estimated): February 1, 2030
• Last Updated: July 24, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share

Locations

US (1)