Abstract 4147473: Development of Pre-clinical Models of Coronary Microvascular Disease

Coronary microvascular disease (CMVD), or disease of the coronary pre-arterioles, arterioles, and capillaries, accounts for 30-50% of ischemic heart disease. Progress in the field requires preclinical models to assess the coronary microvasculature. There are several risk factors for CMVD including age, metabolic syndrome, and hypercholesterolemia. Here, we evaluate the effect of these risk factors on coronary microvascular function in mice. Male and female C57BL/6 mice aged 12-42 weeks (n=29) were treated with 45% high fat diet (HFD) for six months or aged > 9 months. Apolipoprotein E knockout (ApoE-/-) was used to induce hypercholesterolemia as a second risk factor. To assess coronary microvascular function, we measured the intramyocardial blood volume (IMBV) under hyperemic (2.5% isoflurane) and basal (1.25% isoflurane) conditions, as previously reported. Briefly, we labeled red blood cells using pyrophosphate and Technetium 99m-pertechnatate and imaged the heart using µ-SPECT (MI Labs). Coronary microvascular function is reflected by the percent change in intramyocardial activity concentration between rest and stress conditions or △ IMBV. Outliers were removed based on Grubbs method (a=0.1) and groups were compared using Student's T test. p <0.05 was considered significant (Prism 9.3.1). Mice fed HFD had a 0.75-fold change in △ IMBV (23% ± 3.4 vs. 17% ± 2.4, p=0.03). Aging had a similar reduction in △ IMBV, 0.73-fold change (17% ± 2.7, p=0.01). We saw no sex-based difference in △ IMBV in our HFD and aged cohorts (18% vs 19%, 17% vs. 19%, p=0.79, p=0.74 , respectively), consistent with human cardiac perfusion PET imaging data. Exposure to two cardiovascular risk factors, ApoE-/- and HFD (0.48-fold change) or ApoE-/- and aging (0.54-fold change) additionally decreased △ IMBV (11% ± 2.3, p<0.01, 12% ± 2.6, p<0.01, respectively). Of note, ApoE-/- mice on a HFD had no evidence of obstructive epicardial coronary artery disease on histology. We evaluated coronary microvascular function in various mouse models using u-SPECT-based imaging methods and commercially available tracer. Exposure to cardiovascular risk factors induced CMVD, and the degree of CMVD was worse when two cardiovascular insults were used. Further studies using preclinical mouse models of CMVD may be helpful in assessing the effects of therapies and interventions.