LVAD Therapy Induces Changes in Myocardial Glucose Metabolism and Clock Genes

Purpose Myocardial recovery with LVAD therapy is challenging and unpredictable. Next generation sequencing technologies allow for quick, quantitative, and large scale measurements of gene expression in small amounts of tissue. Our primary goal was identify transcriptional changes in response to LVAD therapy. Methods Tissues were collected from patients before and after LVAD placement (n=14) along with controls (n=3). RNASeq analysis was done by using a custom targeted panel on the PGM sequencer. The RNA-sequencing data was filtered to keep the genes with nonzero reads for at least 13 samples per condition. The expression of 140 genes including cardiac, inflammatory and clock genes were analyzed in with non-ischemic dilated cardiomyopathies. The differential expression analysis was conducted using edgeR (Empirical analysis of digital gene expression data in R) package in Bioconductor. The Bejamini-Hochberg method was used to control the false discovery rate (FDR) to be no more than 0.05. Results After filtering there were 122 genes available for analysis. Differential gene expressions were determined between pre- and post- receiving LVAD after adjusting for the patient effect. PDK4 and PER1 were significantly higher post LVAD compared to pre LVAD tissues. Compared to non-failing control tissues, 25 genes were differentially expressed pre-LVAD. These genes included, MYH6, ABCC9, PLEKHA3, ATRLN1, GLS, UBE2B, CCL4 and WEE1. Conclusion PDK4 and PER1 expressions were significantly higher post LVAD. Pyruvate dehydrogenase kinase 4 (PDK4) is a key regulator of glucose metabolism. PER1 is a clock gene exhibiting rhythmic expression in human hearts. It has been shown that PER1 is involved in BP control and regulates renal sodium transport genes. Recent literature suggests that LVAD therapy improves hemoglobin A1C (HbA1c), fasting plasma glucose, and daily insulin requirements. Glucose metabolism and clock proteins are altered with LVAD therapy but numerous other transcriptional changes persist.