Mental Stress Reactivity in Women with Coronary Microvascular Dysfunction

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Project Summary/Abstract: Women with signs and symptoms of myocardial ischemia usually undergo coronary angiography to diagnose obstructive epicardial coronary artery disease (CAD); however, approximately 50% are found to have no obstructive CAD (defined as <50% epicardial stenosis on clinically indicated coronary angiography) and are falsely reassured that their symptoms are non-cardiac. Evidence over the past decade indicates that coronary microvascular dysfunction (CMD)-related ischemia may be an explanation in such cases. CMD is associated with increased risk of major adverse cardiovascular events (MACE) and an estimated 3 million women are impacted by CMD. Cardiac positron emission tomography (PET) imaging can detect CMD by quantifying myocardial flow reserve (MFR). However, therapeutic strategies are poorly developed in CMD, with limited studies to inform clinicians on treatment of CMD. This therapeutic uncertainty results from the fact that the underling pathophysiologic mechanisms of CMD are incompletely understood. Women with CMD typically have a high psychosocial burden and their angina is often induced by psychological stress, which implicates autonomic nervous system (ANS) dysfunction. Our hypothesis is that in CMD women, sympathetic activation during psychological stress drives coronary microvascular constriction. In this proposal we will test the hypothesis 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, ages ≥50 years will be compared: (1) symptomatic women with no obstructive CAD who have CMD (by PET-derived MFR < 2.0) (n=50); (2) symptomatic women with obstructive CAD (n=50); and (3) asymptomatic reference controls (n=50). Both comparison groups will be age-matched to the CMD group. We will assess cardiac sympathetic activity (using123I-meta-iodobenzylguanidine (MIBG) imaging) and autonomic nervous system reactivity to acute mental stress (Aim 1). Vascular reactivity to acute mental stress will also be assessed (Aim 2). In addition to laboratory-induced mental stress, we propose to examine the important role of chronic and daily life stress, negative emotions, anginal symptoms and autonomic imbalance during one week of home monitoring using wearable sensors and a smartphone for real-time data collection (Aim 3). Anginal hospitalization and quality of life will be assessed at 12 months of follow-up, along with MACE. Accomplishing these aims will provide the critically important missing link of whether exaggerated sympathetic activity is predominant in women with CMD. Findings from this work will inform future intervention efforts centered on the utility of ANS modulation for the management of this high-risk, understudied patient group.