Abstract 18970: Development of Therapeutic Strategies for Takotsubo Syndrome

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Introduction: Takotsubo syndrome (TS) results from an aberrant response to stimulation of myocardial NOS-coupled β2-adrenoceptors, occurring most commonly in the ageing female heart. TS is also associated with myocardial inflammation, with biochemical and immunohistochemical evidence of nitrosative stress and resultant activation of the energy-depleting enzyme poly(ADP-ribose) polymerase (PARP-1). Clinically, the main problems associated with TS are (i) impaired LV systolic function, which resolves slowly and (ii) risk of arrhythmic death, particularly in the early course of TS.

Hypothesis: In the current study, we sought to compare the effects on mortality and short term LV systolic dysfunction of two interventions affecting the signal transduction pathway initiated by aberrant β2-adrenoceptor stimulation. Nω-Nitro-L-arginine methyl ester hydrochloride (LNAME) inhibits β2-adrenoceptor-coupled NOS stimulation, while 3-aminobenzamide (3AB) limits activation of PARP-1 secondary to nitrosative stress.

Methods: Female rats aged 4-5 months were treated with either isoproterenol alone (ISO), or ISO plus the NOS inhibitor LNAME (ISO/LNAME), or ISO plus PARP-1 inhibitor 3AB (ISO/3AB). Early (presumably arrhythmic) mortality and impairment of LV systolic function over 24 hours was determined.

Results: ISO caused significant reduction in apical strain rate, apical fractional shortening and a significant increase in mean apical wall thickness (p < 0.01 for all). Results of potential therapeutics are summarised in the Table.

Conclusions: Early mortality in this model of TS is NOS-dependent, suggesting that formation of peroxynitrite may be a crucial determinant. However, myocardial functional impairment appears to reflect largely the activation of PARP-1, with resultant energetic impairment.

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