Abstract 903: Treatment With Anti-oxidant N-acetylcysteine Attenuates Cardiac Hypertrophy And Fibrosis And Improves Susceptibility To Cardiac Arrhythmias In The β-myosin Heavy Chain-Q403 Transgenic Rabbit Model Of Human Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a disease of mutant sarcomeric proteins. The phenotype is characterized by hypertrophy, fibrosis, myocyte disarray and arrhythmias. Hypertrophy and fibrosis are associated with sudden cardiac death and heart failure in HCM and in other forms of cardiovascular diseases. Molecular pathogenesis of HCM is largely unknown. We have shown increased myocardial levels of lipid peroxides, markers of oxidative stress, in the β-myosin heavy chain-Q403 transgenic rabbit model of human HCM. The finding led us to postulate treatment with anti-oxidant N-acetylcysteine (NAC) could attenuate established cardiac phenotype in HCM. Thus, in a randomized study, we treated transgenic rabbits exhibiting HCM with either NAC or a placebo (PL) for 14 months (N=10 per group). Compared to non-transgenics (NTG), baseline septal thickness (ST) and left ventricular mass (LVM) were increased in the PL and NAC groups (ST:2.20±0.19 vs. 2.7± 0.48 vs. 3.02±0.44 mm, p=0.0003 and LVM:3.84±0.85 vs. 5.16±1.22 vs. 6.25±.89 g, respectively, p=0.0005). NAC normalized ST (2.18±0.16 mm) and LVM (3.87±0.37 g), while ST (3.23±.44) and LVM (7.38±2.10) increased further in the PL (all p<0.001). Concordantly, NAC reduced myocyte cross sectional area (NTG:4284±325, PL:5152±359, NAC:4509±167 pixels, p=0.0065), and collagen volume fraction (3.76±.87 vs. 9.9±1.97 vs. 4.5±1.3%, p<0.0001) but not disarray. Oxidized/total glutathione plasma levels were increased in the PL but normal in the NAC groups (NTG:0.006±0.002, PL:0.013±0.0.007, NAC:0.006±0.004, p=0.015). Co-immunoprecipitation of sarcomeric proteins with an anti-glutathione antibody showed a 3-fold increase in glutathionylated sarcomeric α-actin levels in the NAC group. Optical mapping with voltage-sensitive dye showed a 2-fold increase in the upper limit of vulnerability in the PL as compared to NTG (13.3±2 vs. 7.4±2.3, p<0.001). It was reduced with NAC (9.8±2.7, p<0.05 compared to PL). Action potential duration restitution curves and anisotropy were unchanged. The results show attenuation and reversal of established cardiac phenotype in a transgenic rabbit model of human HCM with NAC and beckon the need for clinical studies to test its potential therapeutic effects in humans with HCM.