Single-Nucleus RNA-Seq of Human and Rat Cardiomyocytes Identifies Shared and Distinct Regulators and Features of Aging and Disease

Age is the greatest risk factor for cardiovascular diseases, including heart failure (HF), which is a leading cause of morbidity and mortality. While left ventricular fibrosis, hypertrophy and decreased contractility are associated with cardiac aging, age is not sufficient for HF development. Despite diminished cardiomyocyte (CM) function being central to cardiac pathology, whether factors predisposing the aged CM to disease are the same or distinct from those underlying disease are not determined. To address this, we integrated our own and published single-nucleus RNA-Seq data of different cardiomyopathies and from young and old human samples and probed for unique and overlapping features. To test the utility of rodents for modelling human aging and disease, we compared human data with data from deeply phenotyped relevant rat models. We identified diverse CM substates, which were significantly altered in proportion with pathology in human and in both pathology and age in rat. In human and rat, CM exhibited substantial transcriptomic changes with age and pathology. In addition to established hallmarks of cardiomyopathy and aging, we detected etiology/age-specific differentially expressed genes/pathways and identified candidate nodal regulators underlying these changes. In human and rat, CM exhibited greater cellular and transcriptional heterogeneity in pathology and age. While rats showed substantial differences to humans, overlapping features, including increased CM heterogeneity and altered expression of genes related to epigenetic, fibrotic and hypertrophic remodelling, were also detected. Although some pathways, differentially expressed genes and trajectories are shared between age and pathology, unique aspects support age and pathology as distinct entities.