Background

Human heart failure is characterized by global alterations in the myocardial DNA methylation profile, yet little is known about epigenetic regulation of non-coding transcripts and potential reversibility of DNA methylation with left ventricular assist device (LVAD) support.

Method

Genome-wide mapping of myocardial DNA methylation was performed in 36 patients with end-stage heart failure at the time of LVAD implant, 8 patients at the time of LVAD explant, and 7 non-failing controls using high-density bead array platform. Transcriptomic and functional studies were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSCs).

Results

Etiology-specific analysis revealed 2079 differentially methylated positions (DMPs) in ischemic cardiomyopathy (ICM) and 261 DMPs in non-ischemic cardiomyopathy (NICM). 192 DMPs were common to ICM and NICM. Analysis of paired samples before and after LVAD support demonstrated reverse methylation of only 3.2% of HF-specific DMPs. Methylation-expression correlation analysis yielded several protein-coding genes that are hypomethylated and upregulated ( HTRA1, FAM65A, FBXO16, EFCAB13, AKAP13, RPTOR ) or hypermethylated and downregulated ( TBX3 ) in ICM and NICM patients. A novel cardiac-specific super-enhancer lncRNA ( LINC00881 ) is hypermethylated and downregulated in the failing human heart. LINC00881 is an upstream regulator of sarcomere and calcium channel gene expression including MYH6, CACNA1C , and RYR2. LINC00881 knockdown significantly reduced peak calcium amplitude in the beating human iPSCs.

Conclusions

Failing human heart exhibits etiology-specific changes in DNA methylation including coding and non-coding regions, which are minimally reversible with mechanical unloading. Epigenetic reprogramming may be necessary to achieve transcriptional normalization and sustained clinical recovery from heart failure.