Calcific aortic valve disease (CAVD) represents a slowly progressive pathologic process associated with major morbidity and mortality. The process is characterized by multiple steps: inflammation, fibrosis, and calcification. Numerous studies focalized on its physiopathology highlighting different “actors” for the multiple “acts.” This paper focuses on the role of the tumor necrosis factor superfamily (TNFSF) members in the pathogenesis of CAVD. In particular, we discuss the clinical and experimental studies providing evidence of the involvement of tumor necrosis factor‐alpha (TNF‐α), receptor activator of nuclear factor‐kappa B (NF‐κB) ligand (RANKL), its membrane receptor RANK and its decoy receptor osteoprotegerin (OPG), and TNF‐related apoptosis‐inducing ligand (TRAIL) in valvular calcification.

Ischemic heart disease is the principal cause of death worldwide and clinically manifests as myocardial infarction (MI), stable angina, and ischemic cardiomyopathy. Myocardial infarction is defined as an irreversible injury due to severe and prolonged myocardial ischemia inducing myocardial cell death. Revascularization is helpful in reducing loss of contractile myocardium and improving clinical outcome. Reperfusion rescues myocardium from cell death but also induces an additional injury called ischemia-reperfusion injury. Multiple mechanisms are involved in ischemia-reperfusion injury, such as oxidative stress, intracellular calcium overload, apoptosis, necroptosis, pyroptosis, and inflammation. Various members of the tumor necrosis factor family play a key role in myocardial ischemia-reperfusion injury. In this article, the role of TNFα, CD95L/CD95, TRAIL, and the RANK/RANKL/OPG axis in the regulation of myocardial tissue damage is reviewed together with their potential use as a therapeutic target.