Transcriptional Profiling by Direct Digital Mrna Detection Indicates Heart Failure Recovery is Incomplete Post Lvad Therapy

Introduction: Recovery from end-stage heart failure (HF) with left ventricular assist device (LVAD) therapy remains uncommon. In this study we compared targeted gene expression profiles of pre LVAD, post LVAD and non-failing (NF) hearts utilizing direct mRNA detection of HF specific genes. Our goal was to identify molecular mechanisms involved in HF and responses to LVAD therapy. Method: Myocardial RNAs were isolated from non-ischemic dilated cardiomyopathy patients at LVAD placement and during transplant (n=10) along with NF controls (n=6). NanoString analysis was used to compare gene expression between groups for 126 heart failure specific genes. NanoString mRNA raw count data were preprocessed and normalized using nSolver 4.0 Analysis Software. At least a 2 fold change in gene expression with a FDR adjusted p<0.05 was considered as significant. Ingenuity Pathway Analysis (IPA) was completed to understand the biological pathways involved. Results: Our sample population was 90% male, average age of 56 and 100% Caucasian. In the HF populations average ejection fraction was low <25% and average NYHA was 3.5. In HF, expressions of contractile muscle (MYH6), ion channels protein (KCNIP2) and Ca ATPase (SERCA2) were significantly down regulated when compared to NF controls. Natriuretic peptides (NPPA, NPPB), troponin 1 (TNNI3), nuclear kinases (WEE) and metabolic genes (ATRNL1) were upregulated compared to NF hearts. These differential changes in gene expression persisted post LVAD therapy. There were no significant changes in gene expression between pre and post LVAD HF patients. Ingenuity pathway analysis revealed that these changes in gene expression predispose to arrhythmias. Conclusion: Transcriptional changes in HF specific genes persist in many patients post LVAD therapy contributing to incomplete recovery of end stage heart failure and ongoing risk of arrhythmias. These genes are involved in contractile function, calcium handling and ion channels. Direct digital mRNA detection allows for serial analysis of targeted HF specific genes without reverse transcription and amplification of resultant cDNA. New therapies are needed to reverse adverse molecular changes and improve outcomes in heart failure patients who receive LVADs.