Conner Jackson

Background: Coronary microvascular dysfunction (CMD) is a major contributor to heart disease, especially in patients with non-obstructive coronary artery disease.¹ Structural and functional defects of the coronary microvasculature, oxidative stress, inflammation, diabetes, and dyslipidemia contribute to the development of CMD. Although CMD is clinically significant, around 30 million individuals, current treatments are nonspecific and adapted from treatments for obstructive disease.² Variable presentation and a lack of specific therapies make diagnosis and treatment difficult. Because of the overlap in symptoms and risk factors with other heart diseases, a better understanding of lipid-mediated mechanisms is necessary for the advancement of CMD treatment.⁵

Objective: In this literature review, we explored the mechanisms by which lipid levels and their metabolism contribute to coronary microvascular dysfunction.

Methods: A comprehensive online search in the PubMed database was conducted from 2017 to 2024 using the following keywords: “lipids,” “Coronary microvascular dysfunction,” “endothelium,” and “lipidomics.”

Results: In both in vitro and in vivo samples, increased levels of free fatty acids (FFAs) were shown to suppress AMP-activated protein kinase (AMPK) expression, leading to Krüppel-like factor 2 (KLF2) downregulation and subsequent diminished endothelial nitric oxide synthase (eNOS) levels.⁵ Overexpression of AMPK and KLF2 decreased reactive oxygen species (ROS), alleviated endothelial cell dysfunction, promoted vasodilation, and improved FFA-induced CMD.⁵ Mice fed with a hypercholesterolemic diet showed increased coronary arteriolar inflammation, increased myocardial inflammatory cell infiltration, steatohepatitis, and decreased coronary flow reserve.⁶ 7-ketocholesterol, a metabolite of LDL cholesterol, increased ROS, inflammatory responses, activation of transcriptional factor EB (TFEB), and subsequent lysosomal signaling.⁶ When Bafilomycin A1 was added to cultured mouse cardiac endothelial cells with 7-ketocholesterol, decreased TFEB activation, increased inflammation, and cell death were seen.⁶ When ezetimibe was added to the same culture with 7-ketocholesterol, activation of TFEB was increased, but ROS and inflammation were decreased.⁶ The addition of bafilomycin A1 to mouse cardiac endothelial cell culture decreased the anti-inflammatory effects through the TFEB-lysosomal pathway by inhibiting the lysosomes.⁶ The addition of ezetimibe to the mouse culture increased the activation of TFEB-lysosomal signaling, which increased its anti-inflammatory effects while simultaneously preventing the ROS and inflammation induced by 7-ketocholesterol.⁶ Diabetic mice showed a downregulation of human antigen R (HuR) and decreased expression of connexin 40 (Cx40).⁷ HuR-KO mice exhibited a significant decrease in coronary flow velocity reserve (CFVR), which is a determinant of coronary microvascular function, and capillary density.⁷ Similarly, Cx40-KO mice showed reductions in CFVR and capillary density, but Cx40 overexpression led to increased capillary density and enhanced CFVR.⁷ There were lower concentrations of long-chain triacylglycerols and diacylglycerols and higher concentrations of short-chain triacylglycerols in patients with CMD.⁸ The lipid with the highest correlation with CMD was diacylglycerol with stearic acid and linoleic acid; this lipid classified all participants with CMD correctly.⁸

Conclusions: CMD is a complex disease with many factors involved, such as inflammation, endothelial cell disruption, dyslipidemia, and lipid metabolism. CMD can be a result of many different mechanisms, including the downregulation of the AMPK/KLF2/eNOS pathway, the TFEB-lysosomal pathway, and HuR/Cx40 interactions. Additionally, identifying a lipidomic pattern in those with CMD can serve as an early detector of the disease and allow earlier intervention. More research is needed to turn these findings into a specific, more effective treatment for CMD.

Work Cited:

1. Masi S, Rizzoni D, Taddei S, et al. Assessment and pathophysiology of microvascular disease: recent progress and clinical implications. Eur Heart J. 2021;42(26):2590-2604. doi:10.1093/eurheartj/ehaa857​
2. Sinha A, Rahman H, Perera D. Coronary microvascular disease: current concepts of pathophysiology, diagnosis and management. Cardiovasc Endocrinol Metab. 2020;10(1):22-30. Published 2020 Jul 16. doi:10.1097/XCE.0000000000000223​
3. Del Buono MG, Montone RA, Camilli M, et al. Coronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021;78(13):1352-1371. doi:10.1016/j.jacc.2021.07.042​
4. Millan-Orge M, Torres-Peña JD, Arenas-Larriva A, et al. Influence of dietary intervention on microvascular endothelial function in coronary patients and atherothrombotic risk of recurrence. Sci Rep. 2021;11(1):20301. Published 2021 Oct 13. doi:10.1038/s41598-021-99514-3​
5. Zhang Y, Zhao J, Ren C, et al. Free fatty acids induce coronary microvascular dysfunction via inhibition of the AMPK/KLF2/eNOS signaling pathway. Int J Mol Med. 2023;51(4):34. doi:10.3892/ijmm.2023.5237​
6. Wang Y, Moura AK, Zuo R, et al. Coronary Microvascular Dysfunction Is Associated With Augmented Lysosomal Signaling in Hypercholesterolemic Mice. Journal of the American Heart Association. Published online November 27, 2024. doi:https://doi.org/10.1161/jaha.124.037460​
7. Si R, Cabrera JTO, Tsuji-Hosokawa A, et al. HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes. JCI Insight. 2021;6(21). doi:https://doi.org/10.1172/jci.insight.147982​
8. Lindner JR, Davidson BP, Song Z, et al. Plasma Lipidomic Patterns in Patients with Symptomatic Coronary Microvascular Dysfunction. Metabolites. 2021;11(10):648. Published 2021 Sep 22. doi:10.3390/metabo11100648