Linking coronary microvascular structure and function in preclinical models of coronary microvascular disease
- 1University of Pennsylvania Perelman School of Medicine
Abstract
Despite growing awareness of the importance of the coronary microvasculature in cardiac health and disease, Coronary Microvascular Disease (CMVD) remains poorly understood, underdiagnosed, and without targeted therapies. Preclinical models and quantitative tools to measure CMVD are needed. Here, we use two novel quantitative methods to assess coronary microvascular structure (multi-fractal spectrum analysis) and function (Single Photon Emission Computed Tomography (SPECT)-based intramyocardial blood volume (IMBV) imaging) in mouse models of CMVD. Change in IMBV ({bigtriangleup}IMBV), which serves as a quantitative measure of vasodilatory capacity or microvascular function, was reduced with aging, driven by a significant decrease in female mice. Male mice on ApoE-/- background, fed a high-fat diet (HFD) for 6 months, or both had significantly reduced {bigtriangleup}IMBV. We used immunofluorescence to assess both traditional capillary density and global branching structure and vessel heterogeneity using multifractal spectrum analysis. Both were significantly reduced in all groups, and linear regression modeling showed that they were independently associated with {bigtriangleup}IMBV. Finally, we used {bigtriangleup}IMBV to assess the effects of widely used control Adeno-associated viral (AAV) vectors on coronary microvascular function. AAV-overexpression of GFP did not affect function, but Cre-recombinase compromised coronary microvascular structure and function by 16 weeks. In summary, quantitative assessments of coronary microvascular structure and function highlight changes consistent with CMVD seen with aging, female sex, and metabolic insults. Functional changes are partially driven, but not fully defined, by changes in the underlying structure, highlighting the important and incomplete link between structure and function.
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BibTeX
@misc{kumar2026linking,
title = {{Linking coronary microvascular structure and function in preclinical models of coronary microvascular disease}},
author = {M. B. Kumar and V. Kanangat and M. Woods and O. Lopez and L. Li and E. Blankemeyer and D. M. Conlon and U. George and S. D. Metzler and M. A. Guerraty},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.748256},
url = {https://www.biorxiv.org/content/10.64898/2026.08.31.748256v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Linking coronary microvascular structure and function in preclinical models of coronary microvascular disease
AU - M. B. Kumar
AU - V. Kanangat
AU - M. Woods
AU - O. Lopez
AU - L. Li
AU - E. Blankemeyer
AU - D. M. Conlon
AU - U. George
AU - S. D. Metzler
AU - M. A. Guerraty
PY - 2026
DA - 2026/08/31
PB - bioRxiv
DO - 10.64898/2026.08.31.748256
UR - https://www.biorxiv.org/content/10.64898/2026.08.31.748256v1
AB - Despite growing awareness of the importance of the coronary microvasculature in cardiac health and disease, Coronary Microvascular Disease (CMVD) remains poorly understood, underdiagnosed, and without targeted therapies. Preclinical models and quantitative tools to measure CMVD are needed. Here, we use two novel quantitative methods to assess coronary microvascular structure (multi-fractal spectrum analysis) and function (Single Photon Emission Computed Tomography (SPECT)-based intramyocardial blood volume (IMBV) imaging) in mouse models of CMVD. Change in IMBV ({bigtriangleup}IMBV), which serves as a quantitative measure of vasodilatory capacity or microvascular function, was reduced with aging, driven by a significant decrease in female mice. Male mice on ApoE-/- background, fed a high-fat diet (HFD) for 6 months, or both had significantly reduced {bigtriangleup}IMBV. We used immunofluorescence to assess both traditional capillary density and global branching structure and vessel heterogeneity using multifractal spectrum analysis. Both were significantly reduced in all groups, and linear regression modeling showed that they were independently associated with {bigtriangleup}IMBV. Finally, we used {bigtriangleup}IMBV to assess the effects of widely used control Adeno-associated viral (AAV) vectors on coronary microvascular function. AAV-overexpression of GFP did not affect function, but Cre-recombinase compromised coronary microvascular structure and function by 16 weeks. In summary, quantitative assessments of coronary microvascular structure and function highlight changes consistent with CMVD seen with aging, female sex, and metabolic insults. Functional changes are partially driven, but not fully defined, by changes in the underlying structure, highlighting the important and incomplete link between structure and function.
ER -