Women's Ischemia Syndrome Evaluation (WISE) - Coronary Microvascular Dysfunction (CMD) and Heart Failure With Preserved Ejection Fraction (HFpEF)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 220
- 试验地点
- 2
- 主要终点
- Cardiovascular (CV) events
研究概览
简要总结
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:
- Risk factor conditions (hypertension, dyslipidemia, dysglycemia, loss of estrogen) promote an inflammatory and pro-oxidative state making the microvasculature vulnerable;
- Vulnerable coronary microvasculature becomes dysregulated (sympathetic nervous system activation, endothelial dysfunction, changes in vascular smooth muscle activation, spasm) causing repeated episodes of transient ischemia;
- Repeated ischemia-reperfusion episodes facilitate preconditioning with preservation of cardiomyocyte contractile and microvascular function against ischemic injury;
- Ischemia-reperfusion and preconditioning lead to cardiomyocyte fat accumulation and relaxation impairment resulting in diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF).
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •For the new cohort n=120 women undergoing coronary angiography:
- •Symptomatic angina or anginal equivalent
- •Participant is willing to give written informed consent
- •For the cohort n=100 women and men hospitalized for HFpEF (defined by ESC guidelines):
- •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
排除标准
- •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/m
- •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
研究组 & 干预措施
Women
Women undergoing clinically-ordered coronary angiography for signs and symptoms of ischemia who have no obstructive coronary artery disease (CAD)
干预措施: Coronary Angiography (Procedure)
Women
Women undergoing clinically-ordered coronary angiography for signs and symptoms of ischemia who have no obstructive coronary artery disease (CAD)
干预措施: Coronary Reactivity Testing (Procedure)
Women
Women undergoing clinically-ordered coronary angiography for signs and symptoms of ischemia who have no obstructive coronary artery disease (CAD)
干预措施: Cardiac Magnetic Resonance Imaging (Procedure)
Women
Women undergoing clinically-ordered coronary angiography for signs and symptoms of ischemia who have no obstructive coronary artery disease (CAD)
干预措施: Cardiac Magnetic Resonance Angiography (Procedure)
Women
Women undergoing clinically-ordered coronary angiography for signs and symptoms of ischemia who have no obstructive coronary artery disease (CAD)
干预措施: Rest-Stress Millar Testing (Procedure)
Women
Women undergoing clinically-ordered coronary angiography for signs and symptoms of ischemia who have no obstructive coronary artery disease (CAD)
干预措施: Aortic vasorelaxation tests (Procedure)
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
干预措施: Cardiac Magnetic Resonance Imaging (Procedure)
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
干预措施: Cardiac Magnetic Resonance Angiography (Procedure)
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
干预措施: Computed Coronary Tomographic Angiography (Procedure)
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
干预措施: Rest-Stress Millar Testing (Procedure)
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
干预措施: Aortic vasorelaxation tests (Procedure)
结局指标
主要结局
Cardiovascular (CV) events
时间窗: up to 30 years
次要结局
- Persistent Chest Pain Symptoms: WISE female angina Questionnaire(Up to 30 years)
- Quality of Life Outcomes: SAQ(up to 30 years)
- Persistent Chest Pain Symptoms: SAQ(up to 30 years)
- Quality of Life Outcomes: DASI(up to 30 years)
研究者
Noel Bairey Merz
Director
Cedars-Sinai Medical Center