Heidi Noels

The cardiorenal syndrome (CRS) is described as a multi-organ disease encompassing bidirectionally heart and kidney. In CRS type 4, chronic kidney disease (CKD) leads to cardiac injury. Different pathological mechanisms have been identified to contribute to the establishment of CKD-induced cardiomyopathy, including a neurohormonal dysregulation, disturbances in the mineral metabolism and an accumulation of uremic toxins, playing an important role in the development of inflammation and oxidative stress. Combined, this leads to cardiac dysfunction and cardiac pathophysiological and morphological changes, like left ventricular hypertrophy, myocardial fibrosis and cardiac electrical changes. Given that around 80% of dialysis patients suffer from uremic cardiomyopathy, the study of cardiac outcomes in CKD is clinically highly relevant. The present review summarizes clinical features and biomarkers of CKD-induced cardiomyopathy and discusses underlying pathophysiological mechanisms recently uncovered in the literature. It discloses how animal models have contributed to the understanding of pathological kidney–heart crosstalk, but also provides insights into the variability in observed effects of CKD on the heart in different CKD mouse models, covering both “single hit” as well as “multifactorial hit” models. Overall, this review aims to support research progress in the field of CKD-induced cardiomyopathy.

Atherosclerosis is a chronic inflammatory condition of our arteries and the main underlying pathology of myocardial infarction and stroke. The pathogenesis is age‐dependent, but the links between disease progression, age, and atherogenic cytokines and chemokines are incompletely understood. Here, we studied the chemokine‐like inflammatory cytokine macrophage migration inhibitory factor (MIF) in atherogenic Apoe − / − mice across different stages of aging and cholesterol‐rich high‐fat diet (HFD). MIF promotes atherosclerosis by mediating leukocyte recruitment, lesional inflammation, and suppressing atheroprotective B cells. However, links between MIF and advanced atherosclerosis across aging have not been systematically explored. We compared effects of global Mif ‐gene deficiency in 30‐, 42‐, and 48‐week‐old Apoe − / − mice on HFD for 24, 36, or 42 weeks, respectively, and in 52‐week‐old mice on a 6‐week HFD. Mif ‐deficient mice exhibited reduced atherosclerotic lesions in the 30/24‐ and 42/36‐week‐old groups, but atheroprotection, which in the applied Apoe − / − model was limited to lesions in the brachiocephalic artery and abdominal aorta, was not detected in the 48/42‐ and 52/6‐week‐old groups. This suggested that atheroprotection afforded by global Mif ‐gene deletion differs across aging stages and atherogenic diet duration. To characterize this phenotype and study the underlying mechanisms, we determined immune cells in the periphery and vascular lesions, obtained a multiplex cytokine/chemokine profile, and compared the transcriptome between the age‐related phenotypes. We found that Mif deficiency promotes lesional macrophage and T‐cell counts in younger but not aged mice, with subgroup analysis pointing toward a role for Trem2 + macrophages. The transcriptomic analysis identified pronounced MIF‐ and aging‐dependent changes in pathways predominantly related to lipid synthesis and metabolism, lipid storage, and brown fat cell differentiation, as well as immunity, and atherosclerosis‐relevant enriched genes such as Plin1 , Ldlr, Cpne7, or Il34, hinting toward effects on lesional lipids, foamy macrophages, and immune cells. Moreover, Mif ‐deficient aged mice exhibited a distinct plasma cytokine/chemokine signature consistent with the notion that mediators known to drive inflamm'aging are either not downregulated or even upregulated in Mif ‐deficient aged mice compared with the corresponding younger ones. Lastly, Mif deficiency favored formation of lymphocyte‐rich peri‐adventitial leukocyte clusters. While the causative contributions of these mechanistic pillars and their interplay will be subject to future scrutiny, our study suggests that atheroprotection due to global Mif ‐gene deficiency in atherogenic Apoe − / − mice is reduced upon advanced aging and identifies previously unrecognized cellular and molecular targets that could explain this phenotype shift. These observations enhance our understanding of inflamm'aging and MIF pathways in atherosclerosis and may have implications for translational MIF‐directed strategies.