Multimodality Imaging of Inflammation and Ventricular Remodeling in Pressure Overload Heart Failure

Abstract

Inflammation contributes to ventricular remodeling after myocardial ischemia, but its role in non-ischemic heart failure is poorly understood. Local tissue inflammation is difficult to assess serially during pathogenesis. While ¹⁸F-fluorodeoxyglucose (FDG) accumulates in inflammatory leukocytes which may identify inflammation in the myocardial microenvironment, it remains unclear whether this imaging technique can isolate diffuse leukocytes in pressure overload heart failure. We aimed to evaluate the capability to serially image inflammation with ¹⁸F-FDG in the early stages of pressure overload-induced heart failure, and to compare the timecourse to functional impairment assessed by cardiac magnetic resonance imaging (MRI). Methods: C57Bl6/N mice underwent transverse aortic constriction (TAC, n = 22) or sham surgery (n = 12), or coronary ligation as an inflammation-positive control (n = 5). MRI assessed ventricular geometry and contractile function at d2 and d8 after TAC. Immunostaining identified the extent of inflammatory leukocyte infiltration early in pressure overload. ¹⁸F-FDG PET scans were acquired at d3 and d7 after TAC, under ketamine-xylazine anesthesia to suppress cardiomyocyte glucose uptake. Results: Pressure overload evokes rapid left ventricular dilation compared to sham (end systolic volume, d2: 40.6±10.2µL vs. 23.8 ±1.7µL, p<0.001). Contractile function was similarly impaired (ejection fraction, d2: 40.9 ± 9.7% vs. 59.2 ± 4.4%, p<0.001). Severity of contractile impairment was proportional to histology-defined myocardial macrophage density at d8 (r=-0.669; P = 0.010). Positron emission tomography (PET) imaging identified significantly higher ¹⁸F-FDG accumulation in the left ventricle of TAC compared to sham mice at d3 (10.5±4.1%ID/g vs. 3.8±0.9%ID/g, p<0.001) and at d7 (7.8±3.7%ID/g vs.3.0 ±0.8%ID/g P = 0.006), though the efficiency of cardiomyocyte suppression was variable between TAC mice. The ¹⁸F-FDG signal correlated to ejection fraction (r = -0.75, P = 0.01) and ventricle volumes (r=0.75, p<0.01). Western immunoblotting demonstrated 60% elevation of myocardial glucose transporter 4 expression in the left ventricle at d8 after TAC, indicating altered glucose metabolism. Conclusion: TAC induces rapid changes in left ventricle geometry and contractile function, with a parallel modest infiltration of inflammatory macrophages. Metabolic remodeling overshadows inflammatory leukocyte signal using ¹⁸F-FDG PET imaging. More selective inflammatory tracers are requisite to selectively identify the diffuse local inflammation in pressure overload.