CKD disrupts cardiac energy metabolism and aggravates cardiac inflammation, oxidative stress, and dysfunction post-infarction

Patients with chronic kidney disease (CKD) display a reduced survival following myocardial infarction (MI). As the underlying mechanisms remain unclear, we examined the impact of CKD on cardiac remodeling and function post-MI using a mouse model of adenine-induced CKD.

After MI, CKD mice showed a stronger cardiac dysfunction compared to non-CKD controls. While immunohistochemical and immunofluorescence analyses did not reveal changes in cardiomyocyte apoptosis, infarction size, or myofibroblast content, CKD mice exhibited an increased number of circulating myeloid cells post-infarction and more neutrophil infiltration in the heart. Combining RNAseq, untargeted kinome profiling, western blotting, and mass spectrometry revealed that post-MI, CKD enhanced cardiac oxidative stress and the acute stress complex S100A8/A9 in circulation and the heart, and enforced cardiac MAP-kinase p38 activation and NR4A1 phosphorylation as pathways underlying cardiomyocyte dysfunction. S100A8/A9 also exerted an acute detrimental impact on calcium flux and sarcomere shortening in cardiomyocytes ex vivo. Increased myeloid cell-derived S100A8/A9 expression was confirmed in the infarcted human heart by single-nucleus RNAseq, and CKD patients had higher post-infarction S100A8/A9 levels compared to patients without kidney dysfunction. Furthermore, integrating metabolomics, RNAseq, and mitochondrial analysis uncovered a disturbed cardiac metabolism with impaired glycolysis, a reduced glycerol-3-phosphate-shuttle, and a reduced Coenzyme A-bioavailability in CKD vs. non-CKD mice post-MI. These alterations were associated with poorer cardiac performance post-MI, without intrinsic defects in mitochondrial function observed.

Our study reveals innate immune activation, inflammation, oxidative stress, and metabolic alterations indicative of reduced glycolytic entry and CoA bioavailability along with aggravated cardiac dysfunction post-MI in CKD compared to non-CKD conditions, independent of infarct size, and with poorer cardiac performance in CKD associated with the cardiac metabolic alterations. Combined, this could contribute to the worsened outcome of CKD patients post-MI and reveals cardiac metabolism in CKD as an interesting translational research target.