Abstract 13767: Nitric Oxide Plays a Janus Role in the Pathogenesis of Tako-tsubo Cardiomyopathy

Abstract

Introduction: Tako-tsubo cardiomyopathy (TTC) is fundamentally a catecholamine-stimulated myocardial inflammatory state, initiated by aberrant β2-adrenoceptor signalling in susceptible (usually female) myocardium. We have recently reported that (i) TTC patients exhibit evidence of “supranormal” NO signalling, (ii) at post-mortem, heart of patients dying of TTC have increased content of 3-nitrotyrosine (3NT), a marker of nitrosative stress. Furthermore, in a rat model of TTC, isoproterenol (ISOP) induces increased myocardial expression of both 3NT and thioredoxin-interacting protein (TXNIP), a pro-inflammatory protein normally suppressed by NO. We therefore sought to determine the effects of suppression of NO generation in this rat model. Methods: Female Sprague-Dawley rats, aged 4-5 months, were randomly assigned to one of two groups: ISOP (5mg/kg) (n = 11) and L-NAME (50mg/kg) + ISOP (n = 14). Echocardiography was performed at baseline and after 24 hours. Animals were then sacrificed and immunoblotting was performed in both apical and basal samples to determine the extent of activation of both inducible NO synthase (iNOS) and endothelial NOS (eNOS). Expression of 3NT, TXNIP, and PARP1 as marker of DNA damage were also determined. Results: The results are summarized in the Table: mean ± SE are shown. Furthermore, L-NAME accentuated falls in LVEF and induced marked increases in intraventricular septal wall thickness (p < 0.05 for both). Conclusions: NOS inhibition in this model of TTC limits PARP1 expression and thus potentially conserves energetics, but does not reduce overall nitrosative stress. Moreover, NOS inhibition worsens myocardial inflammation and impairment of LV function. Increased TXNIP expression may reflect withdrawal of NO-mediated inhibition.