A Multimodal Study of Late Gadolinium Enhancement in Uremic Cardiomyopathy: Association of ECM Changes with Gadolinium Deposition

Abstract The aim of this multimodal study was to assess whether gadolinium (Gd) accumulation in uremia-damaged myocardium correlates with late gadolinium enhancement (LGE) patterns and whether Gd localizes within glycosaminoglycan (GAG)-rich regions of the altered extracellular matrix (ECM). An experimental study was conducted on 12 male Wistar rats using an adenine-induced chronic kidney disease (CKD) model to investigate uremic cardiomyopathy-associated ECM changes. Animals were divided into a control group (n = 4) and an adenine diet (AD) group (n = 8) and fed standard chow or a 0.3% adenine diet for up to 10 weeks. Rats received a single dose of gadoversetamide (150–200 μmol/kg, OptiMARK). Health status, body weight, and biochemical parameters were monitored. Hearts were harvested 1.5 h after contrast administration, formalin-fixed, and examined using ex vivo 7 T MR imaging. Adjacent thin sections were taken for multimodal Gd assessment using histology, laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), and synchrotron X-ray fluorescence spectroscopy (SR-μXRF). The AD model reproduced key features of uremic cardiomyopathy, including elevated creatinine, phosphate, and FGF23 levels, consistent with advanced CKD and secondary hyperparathyroidism. AD animals showed increased LV wall thickness to body weight ratios, elevated NT-proBNP, and histological signs of early cardiomyopathy with expanded Alcian-positive (GAG-rich) and collagen-depleted ECM. CMR revealed shortened T1 times and LGE patterns in 7 of 8 AD animals, absent in controls, spatially corresponding to Alcian-positive regions. LA-ICP-MS confirmed increased Gd accumulation in LGE-positive areas. SR-μXRF identified two Gd distribution patterns: extracellular spotty agglomerations within GAG-rich ECM and intracellular accumulations near cardiomyocyte nuclei. Elemental mapping further demonstrated increased myocardial calcium, sulfur, and zinc, with Gd-rich regions overlapping zinc-deficient areas. These findings demonstrate that uremic cardiomyopathy involves ECM remodeling with pathological GAG expansion, which can be detected in vivo by using 7 T CMR. Multimodal analyses indicate that LGE is associated with the spatial distribution of Gd within the GAG-rich ECM and suggest that GAG expansion together with alterations in zinc homeostasis may contribute to local myocardial Gd accumulation.