Background: The process of transition to heart failure (HF) is poorly understood. This study was designed to identify key mechanistic features at different HF stages in severe human aortic stenosis (AS) in order to better understand the pathophysiological process of HF progression.

Methods: The study included 57 AS patients presenting with different degrees of systolic dysfunction at the time of aortic valve implantation. Echocardiographic phenotyping, Next Generation Sequencing (NGS; for RNA, microRNA and DNA methylation/hydroxymethylation) as well as histological analyses (for cellular hypertrophy, fibrosis and differentiation of inflammatory cells) were performed in left ventricular (LV) myocardial biopsies of respective patient subsets.

Results: Through comprehensive cardiac remodeling assessment including Principal Component Analysis (PCA), we were able to determine three major stages of HF progression: i) AS with normal ejection fraction (ASnEF, EF ≥55%) and concentric LV hypertrophy due to increased myocyte size, ii) AS with mildly reduced EF (ASmrEF, EF 45-54%) and LV dilatation, and iii) AS with reduced EF (ASrEF, EF <45%). NGS was used to differentiate the three groups. On a cellular level, inflammatory mast cells dominated in ASmrEF, whereas monocytes and gene expression related to T-lymphocyte activity were found in ASrEF. At the level of epigenetic regulation, histone modification dominated in ASnEF, and microRNAs and DNA methylation/hydroxymethylation in ASrEF. Myocardial fibrosis was found to be significantly increased only in ASrEF.

Conclusions: This study identified LV dilatation as an early feature of HF progression in human AS that is followed by development of cardiac fibrosis and further contractile impairment. Changes in the inflammatory response, epigenetic modifications and extracellular matrix remodeling appear to be critically involved in a stage-specific manner. Our results highlight the need for a more personalized concept of HF therapy what takes into account individual disease stages and distinct, underlying mechanisms.