Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Samit M. Shah

Abstract

EFFECT OF HORMONE EXPOSURE AND MENOPAUSAL STATUS ON MICROVASCULAR DYSFUNCTION AND VASOSPASM

Haleigh T. Larson and Samit M. Shah. Section of Cardiology, Department of Internal Medicine, Yale University, School of Medicine, New Haven, CT

Background: Cardiovascular disease (CVD) is the leading cause of mortality among women in the United States. Ischemic heart disease (IHD) represents a sizeable fraction of CVD that affects women, and ischemia with no obstructive coronary artery disease (INOCA) affects approximately two-thirds of women with IHD. INOCA is characterized by myocardial ischemia symptoms, such as chest pain, without significant epicardial coronary artery obstruction. Up to 50% of patients undergoing coronary angiography for ischemic symptoms are diagnosed with INOCA, and it disproportionately affects women, particularly those undergoing menopause. Women with INOCA experience considerable morbidity, recurrent hospitalizations, compromised quality of life, and elevated cardiovascular risk. Hormonal variations, particularly estrogen fluctuations throughout a woman's lifespan, significantly contribute to sex differences in cardiovascular pathology. In this study, we aim to evaluate the degree of endogenous and exogenous estrogen exposure and ischemic burden in a cohort of women with functional diagnoses of INOCA.

Methods: We created a structured questionnaire designed to gather data on menopausal status at the onset of cardiac symptoms and data on the severity of cardiac symptoms. Over 70 hours of structured interviews were performed using this survey within a cohort of 171 women diagnosed with INOCA, confirmed with invasive coronary function testing. Data from the structured interviews and medical chart review were analyzed to sort participants into discrete menopausal states at the onset of ischemic symptoms: premenopausal, premenopausal on an oral contraceptive pill (OCP), perimenopausal, menopausal, menopausal by surgery, postmenopausal, and postmenopausal on hormone therapy. We then correlated these menopausal states with menopausal symptom burden and INOCA endotype.

Results: Within our cohort of 171 participants, the distribution of menopausal status as ascertained by menopausal symptom index (MENSI) score was as follows: premenopausal (n = 5, 3%), premenopausal on OCP (1, 1%), perimenopausal (3, 2%), menopausal (24, 14%), menopausal by surgery (33, 19%), postmenopausal (88, 51%), and postmenopausal on hormone therapy (17, 10%). Participants classified as menopausal, menopausal by surgery, postmenopausal, and postmenopausal on hormone therapy at the onset of ischemic symptoms were overrepresented as compared to their pre- or perimenopausal counterparts in our INOCA registry. Across the entire cohort, we observed a mean difference of 6.5 years between the onset of vasomotor menopausal symptoms and the onset of ischemic symptoms. Among participants who reported adverse pregnancy outcomes (APO), the mean age of onset of ischemic cardiac symptoms was 55 (n = 42, range: 38 - 67), as compared to participants who did not report any adverse pregnancy outcomes 58 (n = 129, range: 32 - 76). Within the cohort reporting APOs, the mean age of onset of menopausal symptoms in those that endorsed them at the onset of ischemic symptoms was 51 (n = 37, range: 38 - 63), as compared to participants that did not endorse APOs at 55 (n = 134, range: 36 – 64).

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