Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 2 for:    heart failure with preserved ejection fraction, Bairey Merz, Los Angeles | Recruiting, Not yet recruiting Studies | coronary microvascular
Previous Study | Return to List | Next Study

WISE CVD - Continuation (WISE HFpEF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02582021
Recruitment Status : Recruiting
First Posted : October 21, 2015
Last Update Posted : December 17, 2018
Sponsor:
Information provided by (Responsible Party):
Noel Bairey Merz, Cedars-Sinai Medical Center

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. 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).

Condition or disease Intervention/treatment
Microvascular Coronary Dysfunction Cardiovascular Disease Procedure: Coronary Angiography Procedure: Coronary Reactivity Testing Procedure: Cardiac Magnetic Resonance Imaging Procedure: Cardiac Magnetic Resonance Angiography Procedure: Computed Coronary Tomographic Angiography Procedure: Rest-Stress Millar Testing Procedure: Aortic vasorelaxation tests

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.


Layout table for study information
Study Type : Observational
Estimated Enrollment : 220 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Women's Ischemia Syndrome Evaluation (WISE) - Coronary Microvascular Dysfunction (CMD) and Heart Failure With Preserved Ejection Fraction (HFpEF)
Study Start Date : November 2015
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2020

Group/Cohort Intervention/treatment
Women
Women undergoing clinically-ordered coronary angiography for signs and symptoms of ischemia who have no obstructive coronary artery disease (CAD)
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.
Other Name: CRT

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.

Other Name: 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.
Other Name: CMRA

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.
Other Name: Aortic pulse wave velocity-Pulse wave analysis

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

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.

Other Name: 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.
Other Name: CMRA

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.
Other Name: CCTA

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.
Other Name: Aortic pulse wave velocity-Pulse wave analysis




Primary Outcome Measures :
  1. Cardiovascular (CV) events [ Time Frame: up to 5 years ]

Secondary Outcome Measures :
  1. Persistent Chest Pain Symptoms: SAQ [ Time Frame: up to 5 years ]
    Detailed information on chest pain symptoms will include the traditional angina questionnaire. Two SAQ scales measure chest pain: Anginal Stability is a measure of whether a patient's symptoms are changing over time and Anginal Frequency is a measure of how often a patient is having symptoms now.

  2. Persistent Chest Pain Symptoms: WISE female angina Questionnaire [ Time Frame: Up to 5 years ]
    Detailed information on chest pain symptoms will include the WISE female angina questionnaire.

  3. Quality of Life Outcomes: SAQ [ Time Frame: up to 5 years ]
    Quality of life and functional capacity will be collected using the standard instruments of Seattle Angina Questionnaire (SAQ). SAQ scale Quality of Life is a measure of the overall impact of a patient's condition on a patient's interpersonal relationships and state of mind.

  4. Quality of Life Outcomes: DASI [ Time Frame: up to 5 years ]
    Quality of life and functional capacity will be collected using the standard instruments of Duke Activity Status Index for Cardiovascular Diseases (DASI). It is a self-administered questionnaire that measures a patient's functional capacity.


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.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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:

  • Current LVEF <45%
  • 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.
  • Acute coronary syndrome (defined by ACC/AHA guidelines, including MI) within 3 months of entry. Patients who have had an MI or other event within the 6 months prior to entry unless an echo measurement performed after the event confirms a LVEF ≥45%.
  • Primary valvular heart disease (moderate regurgitation or>mild stenosis), primary cardiomyopathies (hypertrophic, infiltrative or restrictive), constrictive pericarditis, high-output heart failure, and right ventricular myopathies)
  • Patients with concurrent cardiogenic shock or requiring inotropic or intra-aortic balloon support or current acute decompensated HF requiring therapy including due to trauma, infection.
  • Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dl, or body mass index (BMI) > 40 kg/m2.
  • Systolic blood pressure (SBP) ≥ 180 mmHg at entry, or SBP >150 mmHg and <180 mmHg at entry unless the patient is receiving 3 or more antihypertensive drugs.
  • 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
  • Contraindications to CMRI, such as internal cardiac defibrillator, untreatable claustrophobia or known angioedema
  • Contraindications to adenosine or regadenoson including severe COPD and asthma.
  • Obstructive stenoses (≥50% luminal diameter stenosis assessed visually at the time of research CTA) will be excluded from further analyses. Subjects with obstructive or borderline obstructive coronary CTA stenoses will be referred to their clinicians for further clinical care and clinical decision making. End stage renal or liver disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02582021


Contacts
Layout table for location contacts
Contact: Ying Mou, PhD 310-248-7669 Ying.Mou@cshs.org
Contact: Sophie Yoo, MS 424-315-4306 Jihye.Yoo@cshs.org

Locations
Layout table for location information
United States, California
Cedars-Sinai Women's Heart Center Recruiting
Los Angeles, California, United States, 90048
Contact: Ying Mou, PhD    310-248-7669    Ying.Mou@cshs.org   
Contact: Sophie Yoo, MS    424-315-4306    Jihye.Yoo@cshs.org   
Principal Investigator: C. Noel Bairey Merz, MD, FACC         
Sponsors and Collaborators
Cedars-Sinai Medical Center
Investigators
Layout table for investigator information
Principal Investigator: C. Noel Bairey Merz, MD, FACC Cedars-Sinai Medical Center

Layout table for additonal information
Responsible Party: Noel Bairey Merz, Director, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT02582021     History of Changes
Other Study ID Numbers: Pro00037321
First Posted: October 21, 2015    Key Record Dates
Last Update Posted: December 17, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by Noel Bairey Merz, Cedars-Sinai Medical Center:
Microvascular Coronary Dysfunction (MCD)
Magnetic resonance imaging (MRI)
Coronary angiography
Coronary Vascular Dysfunction (CVD)

Additional relevant MeSH terms:
Layout table for MeSH terms
Cardiovascular Diseases