Molecular Imaging of Inflammation and Fibrosis in Pressure Overload Heart Failure

Rationale: Tissue inflammation and subsequent fibrosis contribute to ventricle remodelling after ischemic injury and have emerged as viable therapeutic targets. Comparatively, little is understood about the dynamics of inflammation and fibrosis in nonischemic heart failure, which is challenging to interrogate longitudinally. Objective: To investigate the interplay between ventricle loading conditions, tissue inflammation, and progressive fibrosis using noninvasive multimodality molecular imaging to characterize these processes in pressure overload heart failure. Methods and Results: We evaluated cardiac inflammation using positron emission tomography radiotracer ⁶⁸Ga-pentixafor, which binds to chemokine receptor CXCR4 (CXC-motif receptor 4). Over the first 7 days after transverse aortic constriction, CXCR4 imaging identified diffuse elevated myocardial inflammation throughout the left ventricle (+34%, P<0.001), returning to sham levels over 6 weeks after surgery. This transient signal colocalized to local enrichment of CD68 macrophages, as confirmed by autoradiography and immunostaining. Magnetic resonance imaging demonstrated a parallel prolongation of myocardial T1 relaxation time in transverse aortic constriction mice, persisting from 8 days to 6 weeks after surgery (+22%, P=0.003). The persistent imaging signal correlated to increased tissue fibrosis on histology. Molecular imaging at 1 week after surgery correlated independently with the change in ventricle geometry over the subsequent 3 weeks (CXCR4, r^partial=0.670, P=0.024; T1, r^partial=0.689, P=0.019). Alleviation of ventricle pressure by mechanical unloading restored not only cardiac function and geometry but also attenuated global inflammation and normalized T1 relaxation time. This finding demonstrates the capacity to monitor therapeutic intervention by serial molecular imaging. Conclusions: Inflammation and fibrosis are implicated in the early response to pressure overload and may be sensitively monitored by multimodality imaging. Such multimodality molecular imaging approaches may guide novel treatment strategies in nonischemic heart failure. Graphic Abstract: A graphic abstract is available for this article.