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Background— Myocardial expression of endothelin-1 (ET-1) and its receptors ET_A and ET_B is increased in heart failure. However, the role of ET-1 and its signaling pathways in the pathogenesis of myocardial diseases is unclear.

Methods and Results— Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This line (ET⁺) was bred with one harboring cardiac myocyte-restricted expression of tTA (αMHC-tTA). Myocardial ET-1 peptide levels were significantly increased in binary transgenic (BT, ET⁺/tTA⁺) compared with nonbinary transgenic (NBT, ET⁺/tTA⁻; ET⁻/tTA⁺; ET⁻/tTA⁻) or DOX-treated BT littermates (40.1±4.7 versus 2.6±1.2 fmol/mL, P<0.003). BT mice demonstrated progressive mortality between 5 and 11 weeks after DOX withdrawal, associated with left ventricular dilatation and contractile dysfunction (peak +dP/dT, 4673 …