Analysis of genetic variant associated with heart failure mortality implicates thymic stromal lymphopoietin as mediator of strain‐induced myocardial fibroblast‐mast cell crosstalk and fibrosis

Abstract

Heart failure (HF) is a leading cause of death and disability globally. Heritable factors and the extent and pattern of myocardial fibrosis are important determinants of outcomes in patients with HF. In a genome‐wide association study of mortality in HF, we recently identified a genetic polymorphism on chromosome 5q22 associated with HF mortality. Here, we sought to study the mechanisms by which this variant may influence myocardial disease processes. We find that the risk allele is located in an enhancer motif upstream of the TSLP gene (encoding thymic stromal lymphopoietin), conferring increased binding of the transcription factor nescient helix–loop helix 1 (NHLH1) and increased TSLP expression in human heart. Further, we find that increased strain of primary human myocardial fibroblasts results in increased TSLP expression and that the TSLP receptor is expressed in myocardial mast cells in human single nuclei RNA sequence data. Finally, we show that TSLP overexpression induces increased transforming growth factor β expression in myocardial mast cells and tissue fibrosis. Collectively, our findings based on follow‐up of a human genetic finding implicate a novel pathway in myocardial tissue homeostasis and remodeling.