Molecular Imaging of Inflammation and Fibrosis in Pressure Overload Heart Failure

Abstract

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 non-ischemic heart failure, which is challenging to interrogate longitudinally. Objective: To investigate the interplay between ventricle loading conditions, tissue inflammation, and progressive fibrosis using non-invasive 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 CXC-motif receptor 4 (CXCR4). Over the first 7d after transverse aortic constriction (TAC), 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 TAC mice, persisting from 8d 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, rpartial=0.670, p=0.024; T1, rpartial=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 therapeutic approaches in non-ischemic heart failure.

Single-Cell Analysis Revealed the Role of CD8+ Effector T Cells in Preventing Cardioprotective Macrophage Differentiation in the Early Phase of Heart Failure

“…Macrophages have been shown to play essential roles in the pathology of TAC. For example, bone marrow-derived CD72 hi macrophages and CD68 hi inflammatory macrophages have been shown to promote cardiac injury ( 18 , 19 ), while an increased M2-type macrophage count protects against heart injury ( 20 ). T-cell depletion promotes the expression of Csf1 , a macrophage colony stimulating factor (M-CSF) that usually promotes M2 type macrophage differentiation ( 21 ) ( Figures 2A , 3B ).…”

Cardiac Fibroblast Activation in Patients Early After Acute Myocardial Infarction: Integration with MR Tissue Characterization and Subsequent Functional Outcome

“…Clearly, further work is needed to elucidate the relative time course of the cellular, PET-derived signal and the interstitial, CMR-derived signal, along with their importance for functional outcome and for guidance of therapeutic interventions. In this regard, it should be noted that PET with other, immune cell-targeted tracers, may also identify the cellular component of inflammation, for integration with fibrosis-targeted imaging (27,28).…”

Tachycardiomyopathy entails a dysfunctional pattern of interrelated mitochondrial functions

“…The two columns on the left side summarise our results on mitochondrial functions in tachycardiomyopathy. The three columns on the right side compile the current knowledge on main mitochondrial functions in dilated cardiomyopathy (DCM) as well as in heart failure due to coronary artery disease (CAD) or pressure-overload [ 1 , 4 , 7 , 10 , 14 – 16 , 24 – 29 , 37 , 38 , 41 , 48 – 50 , 52 – 55 , 59 , 60 , 62 – 64 , 69 , 70 , 72 , 74 , 76 , 81 , 85 ]. EMID enrichment of mitochondria at intercalated discs, Redox balance ratio of reduced to oxidised nicotinamide adenine dinucleotide, ROS reactive oxygen species, TCA intermediates of the tricarboxylic acid cycle …”