Simultaneous targeting of oxidative stress and fibrosis abrogates 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. In this study, the therapeutic effects of the anti-oxidant, N-Acetylcysteine (NAC) were compared, and combined, with the 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 isoproterenol (ISO; 25mg·kg-1 )-induced cardiac injury for five consecutive days, then left to undergo fibrotic healing until day-14. Sub-groups of ISO-injured mice (n=5-7/group) were treated with either RLX (0.5 mg·kg-1 ·day-1 ), NAC (25 mg·kg-1 ·day-1 ) or both combined; all given subcutaneously via osmotic minipumps from days-7-14. Control mice received repeated saline instead of ISO. KEY RESULTS ISO-injured mice underwent significantly increased LV inflammation (by ~5-fold), oxidative stress (~1-2.5-fold), cardiomyocyte hypertrophy (~25%), cardiac remodelling, fibrosis (~2-2.5-fold) and dysfunction by day-14 post-injury. NAC alone abrogated the cardiomyopathy-induced increase in LV superoxide levels to a greater extent than RLX. Additionally, either treatment alone only partially reduced several measures of LV inflammation, remodelling and fibrosis. In comparison, the combined effects of RLX and NAC completely ameliorated 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 significantly restored the ISO-induced reduction in LV function, without affecting systolic blood pressure. CONCLUSIONS 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.