Abigail Singer

Background: Coronary Microvascular Disease (CMD) is a non-obstructive coronary artery disease characterized by vasospasms, endothelial damage, and ischemia¹. There is a higher incidence in women, with time of onset usually coinciding with menopause, suggesting a sex-specific pathology^2,3,4. It is known that CMD is associated with impairment of estrogen-mediated vasodilation^2,5,6. CMD presents atypically in women with symptoms like neck pain and anxiety and there are no specific diagnostic tests or treatment options^4,5. With a rise in cardiovascular mortality rate in women, there is an increased need to understand what mechanisms related to estrogen signaling contribute to CMD to support development of viable diagnostic and treatment options^4,5. Obesity and diabetes have been found to overcome the known cardioprotection from estrogen and are both associated with increased mineralocorticoid receptor (MR) activation. Therefore, targeting MR signaling has been suggested to offer a sex-specific therapeutic option for CMD and was the focus of this review.

Objectives: The objectives of this review were to explore pathological mechanisms related to obesity and diabetes that contribute to CMD in women and explore sex-specific therapeutic options.

Search methods: Articles on PubMed and Google Scholar were identified by searching within the years 2018-2024 using the keywords “coronary microvascular disease”, “coronary microvascular disease and estrogen”, “sex differences in coronary microvascular disease”, “coronary microvascular disease and mineralocorticoid receptor”, and “coronary microvascular disease and spironolactone”.

Results: The first study sought to identify how MR antagonism provides vascular benefit in obese and diabetic states and found that impaired vasodilation and insulin-induced vasoconstriction in CMD was attenuated by MR antagonism via spironolactone (Sp) treatment⁷. They also found that Sp treatment upregulated antioxidant defense gene networks and downregulated pro-inflammatory and fibrosis-related gene expression^7,9. Another study explored how blocking smooth muscle cell MR (SMC-MR) signaling via gene knockout and Sp treatment affected obesity and diabetes-associated CMD in female mice⁶. They found Sp treatment attenuated endothelial and cardiac dysfunction and improved diastolic function^6,8. They also found the gene knockout group displayed a significant upregulation of estrogen receptor expression and postulated it playing a beneficial role promoting estrogen-signaled cardioprotection⁶. One clinical trial explored the sex-specific benefit of Sp treatment in women and found a significant decrease in cardiovascular and all-cause mortality rates and a significant decrease in multivariate risk for all-cause mortality risk in women in the Sp group¹⁰. These findings suggested that Sp treatment is a promising sex-specific therapy for CMD in women but require further assessment before adopting into clinical practice¹¹.

Conclusion: Emerging evidence supports that MR antagonists provide promising benefits for reducing CMD, vascular remodeling, and mortality rates in women, but further investigations into sex specific responses to spironolactone are required before clinical application. Further investigations are also needed to develop a better idea of how SMC-MR signaling is linked to estrogen in obese and diabetic states. Despite these knowledge gaps, preclinical and clinical literature is increasingly supporting MR antagonism as a potential therapeutic option for CMD for women.

Works cited:

1. Tunc E, Eve AA, Madak-Erdogan Z. Coronary microvascular dysfunction and estrogen receptor signaling. Trends Endocrinol Metab. 2020;31(3):228-238. doi:10.1016/j.tem.2019.11.001
2. Civieri G, Kerkhof PLM, Montisci R, Iliceto S, Tona F. Sex differences in diagnostic modalities of coronary artery disease: Evidence from coronary microcirculation. Atherosclerosis. 2023;384:117276. doi:10.1016/j.atherosclerosis.2023.117276
3. Querio G, Antoniotti S, Geddo F, et al. Ischemic heart disease and cardioprotection: Focus on estrogenic hormonal setting and microvascular health. Vascul Pharmacol. 2021;141:106921. doi:10.1016/j.vph.2021.106921
4. Waheed N, Elias-Smale S, Malas W, et al. Sex differences in non-obstructive coronary artery disease. Cardiovasc Res. 2020;116(4):829-840. doi:10.1093/cvr/cvaa001
5. Majidi M, Eslami V, Ghorbani P, Foroughi M. Are women more susceptible to ischemic heart disease compared to men? A literature overview. J Geriatr Cardiol. 2021;18(4):289-296. doi:10.11909/j.issn.1671-5411.2021.04.004
6. Dona MSI, Hsu I, Meuth AI, et al. Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice. Basic Res Cardiol. 2023;118(1):11. Published 2023 Mar 29. doi:10.1007/s00395-023-00983-6
7. Brown SM, Meuth AI, Davis JW, Rector RS, Bender SB. Mineralocorticoid receptor antagonism reverses diabetes-related coronary vasodilator dysfunction: A unique vascular transcriptomic signature. Pharmacol Res. 2018;134:100-108. doi:10.1016/j.phrs.2018.06.002
8. DuPont JJ, Kim SK, Kenney RM, Jaffe IZ. Sex differences in the time course and mechanisms of vascular and cardiac aging in mice: role of the smooth muscle cell mineralocorticoid receptor. Am J Physiol Heart Circ Physiol. 2021;320(1):H169-H180. doi:10.1152/ajpheart.00262.2020
9. Fraccarollo D, Geffers R, Galuppo P, Bauersachs J. Mineralocorticoid receptor promotes cardiac macrophage inflammaging. Basic Res Cardiol. Published online February 8, 2024. doi:10.1007/s00395-024-01032-6
10. Merrill M, Sweitzer NK, Lindenfeld J, Kao DP. Sex Differences in Outcomes and Responses to Spironolactone in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of TOPCAT Trial. JACC Heart Fail. 2019;7(3):228-238. doi:10.1016/j.jchf.2019.01.003