Distinct Heart Failure Phenotypes Identified by Myocardial Transcriptome Sequencing: Targets for Reverse Remodeling

Purpose Systolic heart failure (HF) is a progressive disease characterized by adverse remodeling from ischemia (ischemic cardiomyopathy, ICM) or a multitude of other causes termed non-ischemic cardiomyopathy (NICM). To accurately characterize the myocardial transcriptome in advanced HF using RNA-sequencing (RNAseq) and identify gene signatures that predict HF phenotypes. Methods RNAseq was performed in myocardial tissue samples obtained at time of left ventricular assist device implant for advanced HF at two sites: the Inova Heart and Vascular Institute (n=39) and University of Utah (n=106). A large number of non-failing (NF) donor hearts (n=35) were also sequenced. Results RNAseq generated ∼26 million reads per sample. The proportion of cardiomyocytes in HF and NF tissues was 81% and 84%. In comparing HF and NF myocardium, there were 105 dysregulated genes (false-discovery rate 1 or Conclusion Advanced HF transcriptomic analysis confirmed that myocardium in ICM and NICM converges to a final common adverse cardiac remodeling pathway. However, within this homogenously ill advanced HF population, two distinct phenotypes were identified with respect to the degree of aberrant gene expression. This differential myocardial transcriptomic signature may identify a HF phenotype that may benefit from targeted therapy to promote reverse remodeling and myocardial recovery.