Wednesday, August 10, 2022
8/10/2022
Project summary This proposal seeks to advance our understanding and treatment of coronary microvascular disease (CMD) through the development of new imaging methods and their use investigating underlying cellular and molecular disease mechanisms (in mouse models), and in the evaluation of pharmacological therapy (in mice and humans). CMD is defined as impaired endothelial-independent coronary microvascular reactivity and is assessed noninvasively by quantitative myocardial perfusion reserve (MPR) imaging using rest and adenosine PET or MRI. While increasingly recognized, the mechanisms that cause CMD are incompletely understood and there are no established therapies. Using preclinical MRI, we have shown that mice fed a high fat high sucrose diet (HFHSD) develop CMD, and also develop increased epicardial adipose tissue (EAT), a reservoir of lipids and inflammatory cells and mediators that shares a microcirculation with the myocardium. Our preliminary data show the remarkable finding that iNOS-/- mice are completely protected from HFHSD-induced CMD. As iNOS is strongly associated with M1-polarized macrophages, and saturated fatty acids (SFAs) are key triggers of M1 macrophage polarization, we hypothesize that EAT SFAs trigger M1 macrophage polarization, increase proinflammatory mediators and iNOS, and lead to coronary microvascular oxidative stress and CMD. MRI is well suited to investigate this system, as MRI can quantify adenosine MPR, myocardial oxidative stress (preclinical), and adipose tissue volume and fatty acid composition. The latter method (MRI of fatty acid composition) has yet to be applied to EAT or accelerated for efficient use in a cardiac MRI protocol. Lastly, SGLT2 inhibitors, known to have beneficial clinical effects on cardiovascular disease, have shown promise in a preclinical study of CMD; however, the effects of SGLT2 inhibitors on CMD and other parameters and the mechanisms of action remain unknown in both mice and human patients. In our project, specific aim 1 is to develop and validate accelerated fatty acid composition (FAC) MRI of epicardial adipose tissue. Specific aim 2 is to use genetically-modified mice to test the hypotheses that (a) an anti-inflammatory fatty acid composition reduces CMD and (b) iNOS expressed by macrophages plays a central role in CMD due to HFHSD. And, specific aim 3 is to test the hypothesis, in mice and humans, that SGLT2 inhibition reduces CMD, and to link the mechanism to EAT and iNOS. The successful completion of these aims will (a) develop broadly applicable MRI methods for FAC imaging of EAT, (b) use imaging to advance our understanding of the cellular and molecular mechanisms underlying CMD, and (c) demonstrate the efficacy and mechanisms of SGLT2 inhibition for the treatment of CMD.
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