The contribution of chronic tobacco exposure in determining post-myocardial infarction (MI) left ventricular (LV) remodeling and possible therapeutic strategies has not been investigated systematically. In this small animal investigation, we demonstrate that chronic tobacco smoke exposure leading up to acute MI in rats is associated with greater histological extent of myocardial necrosis and consequent worse LV function. These findings are associated with increased transcriptomic expression of pro-inflammatory cytokines, tissue repair molecules and markers of oxidative stress in the myocardium. The results demonstrate that an N-acetyl cysteine (NAC) treatment significantly reduced tobacco-exposed induced infarct size and percent fractional shortening. A significantly increased LV end-systolic diameter was observed in tobacco-exposed sham compared to tobacco-naïve sham (4.92 ± 0.41 vs 3.45 ± 0.33; Po0.05), and tobacco-exposed MI compared to tobacco-naïve MI (8.24±0.3 vs 6.1±0.49; Po0.01) rats. Decreased intracardiac mRNA expression of the markers of inflammation, tissue repair and oxidative stress and circulating levels of pro-inflammatory cytokines accompanied these positive effects of NAC. The treatment of tobacco-exposed MI rats with NAC resulted in significantly increased levels of intracardiac mRNA expression of antioxidants, including superoxide dismutase, thioredoxin and nuclear factor-E2-related factor 2, as well as circulating levels of glutathione (7 ± 0.12 vs 10 ± 0.18; Pp0.001), where the levels were almost identical to the tobacco-naïve sham rats. These findings identify a novel post-infarction therapy for amelioration of the adverse effects of tobacco exposure on the infracted myocardium and advocate the use of dietary supplement antioxidants for habitual smokers to prevent and reverse cardiovascular adverse effects in the absence of successful achievement of cessation of smoking. Globally, tobacco smoke exposure remains a significant risk for the development of acute myocardial infarction (MI) irrespective of ethic or gender disparities. Exposure to tobacco smoke increases inflammation, oxidative stress 1-10 and decreases antioxidant expression. [11][12][13][14][15] Direct and indirect studies have demonstrated that oxidative stress from reactive oxygen species (ROS) generated through mitochondria, xanthine oxidase, and the NADPH oxidase system 16-21 is one of the important factors in the pathogenesis of myocardial ischemia. Decreased infarct size in superoxide dismutase (SOD)-producing transgenic mice suggests direct evidence for the role of involvement of ROS in MI. 22,23 In limited investigations, the use of antioxidants such as mercaptopropionyl glycine, edaravone and probucol have demonstrated varied effects on remodeling in animal models of MI, [24][25][26][27][28][29][30][31][32] with improvement in collagen content and histological changes. In this study, we sought to delineate the role of chronic tobacco smoke leading up to an acute MI by focusing on oxidative stress coupled with inflammat...