Simultaneous Targeting Of Oxidative Stress And Fibrosis Reverses Cardiomyopathy-Induced Ventricular Remodelling And Dysfunction

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