TGF-β as a therapeutic target in the infarcted and failing heart: cellular mechanisms, challenges, and opportunities

Introduction: Myocardial fibrosis accompanies most cardiac conditions and can be reparative or maladaptive. Transforming Growth Factor (TGF)-beta is a potent fibrogenic mediator, involved in repair, remodeling, and fibrosis of the injured heart. Areas covered: This review manuscript discusses the role of TGF-beta in heart failure focusing on cellular mechanisms and therapeutic implications. TGF-beta is activated in infarcted, remodeling and failing hearts. In addition to its fibrogenic actions, TGF-beta has a broad range of effects on cardiomyocytes, immune, and vascular cells that may have both protective and detrimental consequences. TGF-beta-mediated effects on macrophages promote anti-inflammatory transition, whereas actions on fibroblasts mediate reparative scar formation and effects on pericytes are involved in maturation of infarct neovessels. On the other hand, TGF-beta actions on cardiomyocytes promote adverse remodeling, and prolonged activation of TGF-beta signaling in fibroblasts stimulates progression of fibrosis and heart failure. Expert opinion: Understanding of the cell-specific actions of TGF-beta is necessary to design therapeutic strategies in patients with myocardial disease. Moreover, to implement therapeutic interventions in the heterogeneous population of heart failure patients, mechanism-driven classification of both HFrEF and HFpEF patients is needed. Heart failure patients with prolonged or overactive fibrogenic TGF-beta responses may benefit from cautious TGF-beta inhibition.