PFKFB3 Inhibitor 3PO Reduces Cardiac Remodeling after Myocardial Infarction by Regulating the TGF-ß1/SMAD2/3 Pathway.

Adverse cardiac remodeling, including cardiac fibrosis, after myocardial infarction (MI) is a major cause of long-term heart failure. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme that regulates glucose metabolism, also plays an important role in various fibrotic and cardiovascular diseases. However, its effects on MI remain unknown. Here, PFKFB3 inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) and a permanent left anterior descending ligation mouse model were used to explore the functional role of PFKFB3 in MI. We showed that PFKFB3 expression increased significantly in the area of cardiac infarction during the early phase after MI, peaking on day 3. 3PO treatment markedly improved cardiac function, accompanied by decreased infarction size and collagen density in the infarct area. Meanwhile, 3PO attenuated cardiac fibrosis after MI by reducing the expression of collagen and fibronectin in murine hearts. Notably, 3PO reduced PFKFB3 expression and inhibited the transforming growth factor-beta 1/mothers against the decapentaplegic homolog 2/3 (TGF-ß1/SMAD2/3) signaling pathway to inhibit cardiac fibrosis after MI. Moreover, PFKFB3 expression in neonatal rat cardiac fibroblasts (NRCFs) increased significantly after MI and under hypoxia, whereas 3PO alleviated the migratory capacity and activation of NRCFs induced by TGF-ß1. In conclusion, 3PO effectively reduced fibrosis and improved adverse cardiac remodeling after MI, suggesting PFKFB3 inhibition as a novel therapeutic strategy to reduce the incidence of chronic heart failure following MI.

The Prognostic Significance of Secondary Mitral Regurgitation in Heart Failure Patients with Varying Estimated Pulmonary Artery Systolic Pressure.

Background: Limited research has been conducted to investigate the impact of secondary mitral regurgitation (MR) in heart failure (HF) patients with different levels of estimated pulmonary artery systolic pressure (ePASP). Methods: A total of 468 patients suffering from HF and secondary MR were enrolled and categorized into non-severe and severe MR groups based on the degree of MR. The primary endpoint of the study was a composite of cardiovascular death and a first-heart-failure hospitalization. The secondary endpoints were the primary outcomes, individually. The outcomes of the two groups were compared. Patients were further classified based on whether their ePASP was ≥ 50 mmHg or < 50 mmHg. Subsequently, the outcomes of the non-severe and severe MR groups were compared within each ePASP category. Results: In a median (SD) follow-up of 694 (410) days, severe MR was associated with higher risk for primary endpoints in patients with heart failure, especially in those with ePASP ≥ 50 mmHg. In patients with ePASP < 50 mmHg, the prognostic value of severe MR was diminished. Conclusions: Assessment of the severity of MR can identify heart failure patients who are at greater risks for poor clinical outcomes. Additionally, the prognostic value of secondary MR was more pronounced in patients with elevated ePASP.