NCT02582021

WISE CVD - Continuation (WISE HFpEF)

Women's Ischemia Syndrome Evaluation (WISE) - Coronary Microvascular Dysfunction (CMD) and Heart Failure With Preserved Ejection Fraction (HFpEF)

• Status: Recruiting
• Phase: —
• Study type: Observational
• Enrollment: 220 (estimated)
• Sponsor: Cedars-Sinai Medical Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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. Risk factor conditions (hypertension, dyslipidemia, dysglycemia, loss of estrogen) promote an inflammatory and pro-oxidative state making the microvasculature vulnerable; 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. Repeated ischemia-reperfusion episodes facilitate preconditioning with preservation of cardiomyocyte contractile and microvascular function against ischemic injury; 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).

Detailed description

The current application will study new cohorts of women and men with the following specific aims: Specific Aim 1: LV diastolic dysfunction is linked to CMD. Sub-Aim 1: LV diastolic dysfunction and CMD are linked via the mechanism of cardiomyocyte fat accumulation. Specific Aim 2: Comprehensive noninvasive Cardiac Magnetic Resonance Imaging (CMRI) that includes LV diastolic function is linked with invasive measures of LV diastolic function and can optimize diagnosis of CMD. Sub-Aim 2: Coronary Magnetic Resonance Angiography (CMRA) can exclude obstructive CAD in CMD. Specific Aim 3: Add completely de-identified data sharing to prepare for future large precision medicine research and to advance precision medicine initiative. Exploratory Aim: Blood proteomic and metabolomics biomarkers of extracellular matrix remodeling and fibrosis combined with ischemia measures will predict HFpEF. In this prospective, cohort design study, investigators intend to enroll 220 new subjects including 120 symptomatic women undergoing invasive coronary angiography for suspected ischemia with no obstructive coronary artery disease (CAD) defined as ≥50% luminal diameter stenosis in ≥1 epicardial coronary artery and 100 women and men hospitalized for Heart Failure with preserved Ejection Fraction (HFpEF) defined by the European Society of Cardiology (ESC) criteria who have not yet undergone coronary angiography. New and existing samples and longer term follow-up will be analyzed in an exploratory fashion looking for potential HFpEF biomarkers for pilot data purposes. After baseline evaluation, the n=120 cohort will undergo noninvasive high resolution, comprehensive CMRI imaging, invasive angiography, coronary reactivity testing and rest-stress Millar pressure-volume measurement. Handgrip, mild leg exercise, and brief Valsalva Maneuver will be conducted during CMRI and Millar pressure-volume assessment to characterize cardiac response to stress. Lastly, these patients will also undergo MR Coronary Angiography, for validation purposes against gold-standard angiography. The cohort of 100 women and men with HFpEF admitted to the hospital who have not yet undergone coronary angiography will also undergo CMRI (with stress), including MR coronary angiography (CMRA) and noninvasive computed coronary tomographic angiography (CCTA)(CSMC only). This will provide understanding of a non-cath-lab based population regarding links between CMD, diastolic function and HFpEF, and will result in data to test the hypothesis that coronary MRA can exclude obstructive CAD and diagnose CMD without ionizing radiation. Proteomic and metabolomics biomarker assays in the (n=567) subjects with no obstructive CAD (Exploratory Aim) will be performed.

Conditions

• Microvascular Coronary Dysfunction
• Cardiovascular Disease

Interventions

Type	Name	Description
PROCEDURE	Coronary Angiography	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.
PROCEDURE	Coronary Reactivity Testing	An angiography procedure specifically designed to examine the blood vessels in the heart and how they respond to different medications.
PROCEDURE	Cardiac Magnetic Resonance Imaging	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.
PROCEDURE	Cardiac Magnetic Resonance Angiography	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.
PROCEDURE	Computed Coronary Tomographic Angiography	Noninvasive, imaging method that uses a computed tomography (CT) scanner to look at the structures and blood vessels of the heart.
PROCEDURE	Rest-Stress Millar Testing	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.
PROCEDURE	Aortic vasorelaxation tests	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.

Timeline

• Start date: 2015-11-01
• Primary completion: 2030-02-01
• Completion: 2030-02-01
• First posted: 2015-10-21
• Last updated: 2025-07-24

Locations

1 site across 1 country: United States