Thus, this study provides evidence that HFpEF results in a systemic pro-inflammatory state, causes excessive ROS production, leads to downregulation of eNOS and myocardial stiffness, inhibits Sirt1 activation, increases Smad3 acetylation, activates the TGF-β signaling pathway, and eventually enhances myocardial fibrosis (Figure 9). The gene discussed is SMAD3; the disease is Myocardial fibrosis.