PROJECT SUMMARY
Insulin resistance (IR) in aging hearts of nondiabetics is known to be promoted by fat accumulation within
senescent myocardium in the absence of obesity or physical inactivity. Importantly, these changes make the
aged myocardium more susceptible to heart failure and sudden death. Similarly, aging of infarcted myocardium
in nondiabetic subjects is commonly accompanied by fat accumulation in myocardial scar tissue (lipomatous
metaplasia, LM). However, whether LM influences myocardial IR, remains unknown. Recent studies using a
nondiabetic rat model have demonstrated direct evidence of selective myocardial IR in chronic MIs with heart
failure. However, it remains unknown whether these MIs also had LM.
Cardiac inflammaging post-MI is a state of chronic low-grade sterile inflammation that plays a key role in the
onset and progression of heart failure. It is a mast cell (MC)- and macrophage (MF)-driven process characterized
by a complex balance between pro- and anti-inflammatory responses. Equally important, the preponderance of
MC and proinflammatory M1 MF within adipose tissue (AT) is now recognized as a hallmark of obesity-
associated low-grade inflammaging which leads to reduced expression of adipocyte glucose transporter (GLUT4)
and systemic IR. Systemic IR has been commonly observed in nondiabetic patients with ischemic post-MI
cardiomyopathy. However, whether these subjects also exhibit myocardial IR and/or LM, is unknown.
Metabolic state and the phenotype of MC and MF throughout the inflammatory process are tightly linked.
While activated MC and M1 MF are highly dependent on glucose as an energy substrate, anti-inflammatory M2
MF are preferentially fueled by fatty acid ß-oxidation. Lipid-overloading and insulin (hyper) stimulation have each
been demonstrated to promote MC activation, M1 polarization, and MF foam cell formation, thus initiating the
process of atherogenesis. Moreover, the pro-atherogenic effects of MCs were shown to be successfully
abolished via MC membrane stabilization. Notably, MC and lipid-laden M1 MF have each been demonstrated
in infarcted territory beyond subacute phase of MI. However, their long-term fate, the interaction between the
two, and their respective roles in LM and/or IR remain unknown.
While 18F-fluorodeoxyglucose (18FDG) PET has emerged as a non-invasive imaging of choice to assess
myocardial immunometabolic state and to diagnose myocardium-specific IR, quantitative cardiac MR (qCMR) is
now widely accepted as the gold standard for the quantitative estimation of infarct size and tissue composition.
Herein, we propose to use a combined 18FDG-PET/qCMR imaging to evaluate the effects of MC stabilization on
metabolic phenotype and remodeling of MI, in a porcine model.
