Aims Deregulation of epigenetic processes and aberrant gene expression are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA methylation in heart failure development. Methods and results We analysed m6A RNA methylation via next‐generation sequencing. We found that approximately one quarter of the transcripts in the healthy mouse and human heart exhibit m6A RNA methylation. During progression to heart failure we observed that changes in m6A RNA methylation exceed changes in gene expression both in mouse and human. RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level mainly represented changes in structural plasticity. Mechanistically, we could link m6A RNA methylation to altered RNA translation and protein production. Interestingly, differentially methylated but not differentially expressed RNAs showed differential polysomal occupancy, indicating transcription‐independent modulation of translation. Furthermore, mice with a cardiomyocyte restricted knockout of the RNA demethylase Fto exhibited an impaired cardiac function compared to control mice. Conclusions We could show that m6A landscape is altered in heart hypertrophy and heart failure. m6A RNA methylation changes lead to changes in protein abundance, unconnected to mRNA levels. This uncovers a new transcription‐independent mechanisms of translation regulation. Therefore, our data suggest that modulation of epitranscriptomic processes such as m6A methylation might be an interesting target for therapeutic interventions.

In current clinical practice, care of diseased patients is often restricted to separated disciplines. However, such an organ‐centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age‐associated dementias. The underlying molecular mechanisms are presently unknown, and thus, corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms, we show that heart failure leads to specific changes in hippocampal gene expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.

24In current clinical practice care of diseased patients is often restricted to separated disciplines. However, 25 such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe 26 burden in heart failure patients. Moreover, these patients have an increased risk for age-associated 27 dementias. The underlying molecular mechanisms are presently unknown and thus corresponding 28 therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model 29 organisms we show that heart failure leads to specific changes in hippocampal gene-expression, a brain 30 region intimately linked to cognition. These changes reflect increased cellular stress pathways which 31 eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster 32 essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory 33 function. These pathological changes are ameliorated via the administration of a drug that promotes 34 neuronal euchromatin formation. Our study provides first insight to the molecular processes by which 35 heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive 36 defects in heart failure patients. 37 38 39 40 41 2 1 2 3 1 Results 2 3 Heart failure in CamkIIδc TG mice leads to hippocampal gene expression changes indicative of 4 dementia 5With the aim to elucidate the molecular processes by which cardiovascular dysfunction leads to memory 6 impairment and an increases the risk for dementia, we decided to employ a well-established mouse 7 model for heart failure in which cardiomyocyte-specific kinase CamkIIδc is overexpressed under the 8 control of the alpha-MHC promoter (CamkIIδc TG mice) (Maier, Zhang et al., 2003). Thus, 9 overexpression of CamkIIδc is specific to cardiomyocytes and is not detected in other organs, including 10 the brain (Maier et al., 2003), making it a bona fide model to study the impact of heart failure on brain 11 function ( Fig 1A). We reasoned that this well-defined genetic heart failure model would be superior to 12 other experimental approaches linked for example to cerebral hypoperfusion such as carotid artery 13 occlusion, since it allowed us to study brain function in response to the very precise and exclusive 14 manipulation of cardiac tissue. In line with previous findings, 3-month-old CamkIIδc TG mice displayed 15 heart failure with left ventricular dilatation, impaired ejection fraction, and increased heart mass ( Fig 1B, 16 C), whereas the overall body weight was not affected (P = 0.863 for CamkIIδc TG vs control mice, n =8, 17 unpaired t-test). As a first approach to study the impact of cardiac dysfunction on brain plasticity we 18 decided to analyze the transcriptome of the hippocampal CA1 region in 3-month-old CamkIIδc TG mice 19 ( Fig 1D). This was based on data showing that (1) gene expression is a sensitive molecular correlate of 20 memory function and is de-regulated in dementia patients and corres...