Coronary Microvascular Dysfunction (CMD) occurs when there are problems in the small blood vessels/arteries of the heart, resulting in persistent chest pain that affects women.

There are an estimated 3 million women in the US with CMD and about 100,000 new cases annually. This research will investigate whether the stress response physiology and autonomic function in response to mental stress are different in women with CMD compared to other groups. The autonomic nervous system (ANS) controls normally involuntary activities, such as heart rate, respiration (breathing), body temperature, blood pressure, and urinary function. This study will also examine how chronic and daily life mental stress affects the heart and blood vessels.

Participants from this study will be recruited mainly from Emory Healthcare-associated hospitals, the Emory Heart Disease Center for Prevention, and Emory Healthcare outpatient cardiology clinics. Participants will have physical exams, blood tests, stress tests, exercise tests, surveys, questionnaires, and images taken of their hearts and blood vessels. They will be asked to take home devices to monitor their autonomic function, sleep, and track their mood, stress level, and symptoms for one week. Data and specimens will be saved for future research.

The overall goal of this project is to clarify the mechanisms and pathophysiology of how psychological stress contributes to Major Adverse Cardiovascular Events (MACE) in women despite having no obstructive CAD. Through this proposal, the research team expects to have an improved understanding of the relationships between mental stress and coronary microvascular dysfunction in women.

One-third to one-half of women with chest pain who are suspected of having myocardial ischemia and undergo coronary angiography are actually found to have no obstructive coronary artery disease (CAD) (<50% luminal stenosis) and thus are often reassured and dismissed without a cardiac diagnosis or therapy. Current evidence suggests that a large proportion of these women have coronary microvascular dysfunction (CMD) and are at significantly increased risk of major adverse cardiovascular events (MACE), including myocardial infarction, heart failure, and sudden cardiac death. However, because of substantial knowledge gaps, these patients also have recurrent hospitalizations for chest pain, reduced health-related quality of life, and comparable disability and healthcare costs to obstructive CAD patients. Cardiac rest/stress positron emission tomography (PET) imaging can detect impaired myocardial flow reserve (MFR) and diagnose CMD. However, therapeutic strategies are poorly developed, with limited studies to inform clinicians on the treatment of CMD.

Comorbid psychological factors such as anxiety and depression are prevalent in women with persistent angina, and stress can contribute to and exacerbate angina, implicating the autonomic nervous system (ANS) as one mechanistic pathway in CMD-related ischemia and MACE. The preliminary data indicate that women with CMD have ANS dysfunction with sympathetic predominance compared to non-CMD controls. The research team has shown that women have more mental stress ischemia (MSI) and stress-induced peripheral microvascular vasoconstriction compared to men. MSI is an important prognostic marker with an estimated two-fold increase in MACE, including mortality, regardless of the severity of CAD.

The research team posits that an improved understanding of psychological stress reactivity in CMD patients will help tease out the underlying mechanisms contributing to adverse outcomes in CMD-related ischemia and provide new treatment targets to reduce symptom burden and MACE. The overall goal of this project is to clarify the mechanisms and pathophysiology of how psychological stress contributes to MACE in women despite having no obstructive CAD. The research team has also shown that coronary microvascular responses to mental stress are reflected in the peripheral microvascular circulation. This proposal addresses an important knowledge gap in an understudied population and is a direct extension of their prior work. Findings from this work have the potential to inform therapeutic strategies in CMD, a problem that impacts an estimated 3 million American women. The unifying hypothesis is that women with CMD have exaggerated sympathetic activation and abnormal vasoreactivity to mental stress, which predisposes them to adverse outcomes even in the absence of obstructive CAD.

Three groups of post-menopausal women will be compared: (1) symptomatic women with no obstructive CAD who have CMD ; (2) symptomatic women with chronic obstructive CAD (oCAD); and (3) asymptomatic control women with no prior history of CAD or angina, who are age-matched to the CMD women. The oCAD group will serve as a comparison group since these women represent the prevailing paradigm of ischemia from obstructive stenosis while sharing common cardiovascular risk factors that could confound the findings.

No study has comprehensively characterized mental stress reactivity by pairing autonomic responses and vascular reactivity in women with CMD, and with follow-up of angina and quality of life (QoL). This study would provide critical data on the clinical significance of these measures in the CMD population.

CMD Group

Inclusion Criteria:

• Symptomatic postmenopausal women with chest pain
• age≥45 years old
• willing to undergo cardiac MIBG scan
• willing to undergo mental stress testing
• competent to give informed consent

Exclusion Criteria:

• Significant epicardial stenosis (defined by coronary stenosis ≥ 70% in any epicardial coronary artery or hemodynamically significant stenosis determined by fractional flow reserve)
• Left ventricular systolic dysfunction (ejection fraction ≤ 50%)
• Heart failure with a preserved ejection fraction
• Significant anemia or blood dyscrasia
• Severe uncontrolled hypertension >180/100
• Unable to lie flat for mental stress testing
• Pre-menopausal
• Pregnant
• Pericarditis/myocarditis
• History of percutaneous coronary intervention
• Coronary artery bypass grafting
• Acute myocardial infarction/acute coronary syndrome/unstable angina within 1 month
• Significant valvular disease, including aortic or mitral stenosis
• Sinus node dysfunction/pacemaker, 2nd or 3rd-degree atrioventricular block
• Severe lung, renal, liver, or psychiatric illness
• Current neoplasm
• History of substance abuse
• Acute illness such as infection in the previous 4 weeks
• Life-expectancy less than 2 years
• Unable to safely withdraw medications for mental stress testing
• Significant psychiatric illness that precludes safe participation in the study
• Conditions that preclude accurate or safe testing and patient refusal
• Unable to consent

Obstructive CAD (oCAD) Group

Inclusion Criteria:

• Symptomatic postmenopausal women with chest pain who have obstructive CAD in at least one epicardial coronary artery
• willing to undergo cardiac MIBG scan
• willing to undergo mental stress testing
• competent to give informed consent

Exclusion Criteria:

• Significant epicardial stenosis (defined by coronary stenosis ≥ 70% in any epicardial coronary artery or hemodynamically significant stenosis determined by fractional flow reserve)
• Left ventricular systolic dysfunction (ejection fraction ≤ 50%)
• Heart failure with a preserved ejection fraction
• Significant anemia or blood dyscrasia
• Severe uncontrolled hypertension >180/100
• Unable to lie flat for mental stress testing
• Pre-menopausal
• Pregnant
• Pericarditis/myocarditis
• History of percutaneous coronary intervention
• Coronary artery bypass grafting
• Acute myocardial infarction/acute coronary syndrome/unstable angina within 1 month
• Significant valvular disease, including aortic or mitral stenosis
• Sinus node dysfunction/pacemaker, 2nd or 3rd-degree atrioventricular block
• Severe lung, renal, liver, or psychiatric illness
• Current neoplasm
• History of substance abuse
• Acute illness such as infection in the previous 4 weeks
• Life expectancy is less than 2 years
• Unable to safely withdraw medications for mental stress testing
• Significant psychiatric illness that precludes safe participation in the study
• Conditions that preclude accurate or safe testing and patient refusal
• Unable to consent

Asymptomatic Control Group

Inclusion Criteria:

• Asymptomatic postmenopausal women, age ≥ 45 years old
• Healthy volunteer with no cardiac risk factors
• No history or diagnosis of heart disease
• Not on any cardiac medications
• Normal maximal exercise treadmill stress testing (ETT)
• Fully understanding and willing to undergo mental stress testing
• Willing to sign the informed consent

Exclusion Criteria:

• Significant epicardial stenosis (defined by coronary stenosis ≥ 70% in any epicardial coronary artery or hemodynamically significant stenosis determined by fractional flow reserve)
• Left ventricular systolic dysfunction (ejection fraction ≤ 50%)
• Heart failure with a preserved ejection fraction
• Significant anemia or blood dyscrasia
• Severe uncontrolled hypertension >180/100
• Unable to lie flat for mental stress testing
• Pre-menopausal
• Pregnant
• Pericarditis/myocarditis
• History of percutaneous coronary intervention
• Coronary artery bypass grafting
• Acute myocardial infarction/acute coronary syndrome/unstable angina within 1 month
• Significant valvular disease, including aortic or mitral stenosis
• Sinus node dysfunction/pacemaker, 2nd or 3rd-degree atrioventricular block
• Severe lung, renal, liver, or psychiatric illness
• Current neoplasm
• History of substance abuse
• Acute illness such as infection in the previous 4 weeks
• Life expectancy is less than 2 years
• Unable to safely withdraw medications for mental stress testing
• Significant psychiatric illness that precludes safe participation in the study
• Orthopedic limitation that will prevent ETT
• LDL >120 mg/dL
• Fasting blood glucose >95 mg/dL
• Hypertension, defined as resting BP >120/80
• Diabetes
• Hyperlipidemia
• Smoking
• Conditions that preclude accurate or safe testing and patient refusal
• Unable to consent

Postmenopausal women

The research team will share de-identified group demographic data and outcomes with the sponsor and other researchers who request access.

The research team will share the data after the study completion and after the initial data is published.

The research team will share the data via secure data transfer