Simultaneous targeting of oxidative stress and fibrosis reverses cardiomyopathy‐induced ventricular remodelling and dysfunction

Background and Purpose Oxidative stress fibrosis are hallmarks of cardiomyopathy-induced heart failure yet not effectively targeted by current frontline therapies. Here, the therapeutic effects anti-oxidant, N-acetylcysteine (NAC), were compared combined with an acute drug established anti-fibrotic effects, serelaxin (RLX), in a murine model cardiomyopathy. Experimental Approach Adult male 129sv mice subjected to repeated isoprenaline (25 mg·kg−1)-induced cardiac injury for five consecutive days then left undergo fibrotic healing until Day 14. Subgroups isoprenaline-injured treated RLX (0.5 mg·kg−1·day−1), NAC mg·kg−1·day−1) or both combined, given subcutaneously via osmotic minipumps from 7 Control received saline instead isoprenaline. Key Results Isoprenaline-injured showed increased ventricular (LV) inflammation (~5-fold), oxidative (~1–2.5-fold), cardiomyocyte hypertrophy (~25%), remodelling, (~2–2.5-fold) dysfunction 14 after injury. alone blocked increase LV superoxide levels, greater extent than RLX. Additionally, either treatment only partly reduced several measures inflammation, remodelling fibrosis. In comparison, combination prevented macrophage infiltration, size, days. The therapy also restored isoprenaline-induced reduction function, without affecting systolic BP. Conclusion Implications These findings demonstrated that simultaneous targeting is key treating pathophysiology induced