Transcriptional Atlas of Cardiac Disease

Cardiovascular diseases (CVD), including diseases of the cardiac muscle (cardiac disease), account for a substantial proportion of global morbidity and mortality. Although there are several life-saving drugs and devices that have improved the prognosis, the improvement in the last decade has stabilized, largely because there are no or very few targeted treatments in the combat against CVD. In search for a better understanding of CVD and new therapeutic targets, basic and mechanistic studies are warranted. One important tool is the use of single-cell and single-nucleus RNA sequencing (snRNAseq) approaches. Several individual diseases and specific phenotypes have been studied in this way, but efforts to pool all of this data into one comprehensive dataset are lacking. We created the first human cardiac disease reference atlas so far, encompassing snRNAseq data from 7 datasets, spanning 8 different cardiac diseases (n=117) and healthy tissues (n=37), with over 1.6 million nuclei. This database integrated datasets of cardiac tissue from patients with atrial fibrillation (AF), acute myocarditis (AM), ischemic heart disease (IHD), myocardial infarction (MI), ACM (arrhythmogenic cardiomyopathy), DCM (dilated cardiomyopathy), HCM (hypertrophic cardiomyopathy) and NCM (noncompaction cardiomyopathy). We revealed transcriptional disparities dividing the diseases into acquired cardiac diseases and (genetic) cardiomyopathies, which was supported by pathway analyses based on the differentially expressed genes. Hallmarks of acquired cardiac diseases were dysregulated cellular communication and motility processes, and a strong proof for the cardiac fibroblast as a central mediator. Cardiomyopathies on the other hand were accompanied by processes involved in the contractile function of the heart, with a high contribution of cardiomyocytes. Employing the novel cardiac atlas to explore if repurposing of drugs may be useful, it was revealed that prime targets for fibroblasts ( ENO2 ) and cardiomyocytes ( HTR5A ) exist. In summary, this atlas represents an important step in cardiac research by recapitulating analyses from various distinct studies and presenting a novel way of gaining insights on multiple cardiac diseases simultaneously.