R01HL168635

Multiparametric PET/MRI assessment of mast cell stabilization effects on inflammaging and glucose utilization in infarcted myocardium - 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 myocardial infarction (MI) 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 β-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 the 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.

Cedars-Sinai Medical Center

NOT APPLICABLE

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Los Angeles, California 900481804 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 98% from $1,669,836 to $3,306,276.