Abstract 5342: Electrical Remodeling Precedes LV Dysfunction in Endothelin-1-Induced Cardiomyopathy
Background: Binary transgenic (BT) mice with conditional cardiac expression of endothelin-1 (ET-1) exhibit a cardiomyopathy with LV dilatation, contractile dysfunction, QRS prolongation, and death following doxycycline (DOX) withdrawal. We hypothesized that ET-1-induced electrical remodeling will:
precede and contribute to the heart failure (HF) phenotype;
be reversible following cessation of ET-1 expression; and
be mediated by disrupted gap junctions.
Methods & Results: BT vs. non-binary transgenic (NBT) littermates were withdrawn from DOX and serially studied with ultrasound biomicroscopy (UBM, 30 MHz), Millar hemodynamics, intracardiac and epicardial mapping, Western blot, and qRT-PCR. Electrical abnormalities were detected as early as 4 wks after ET-1 induction, when cardiac structure and function by UBM remained unaffected. By 6 wks, markers of hypertrophy (βMHC) and HF (BNP) were increased and consistent with unequivocal abnormalities in systolic and diastolic function in BT but not NBT mice. By 8 wks, prolonged PR (79.1±3.2 vs. 62.3±4.7), QRS (17.6±2.2 vs. 9.3±0.4), atrial-His (62.1±3.5 vs. 45.9±3.8) and R-to-L ventricular conduction (16.7±1.6 vs. 11.1±0.8) durations were documented in BT vs. NBT (ms; n=7–8; P≤0.01). We also documented prolonged ventricular activation (27.3±6.2 vs. 5.4±0.5), AV conduction (76.8±7.6 vs. 48.3±2.0) and ventricular depolarization (15.5±1.4 vs. 8.4±0.3) intervals (ms), and reduced minimum dV/dt (25.2±4.4 vs. 88.2±2.7; V/s) in BT vs. NBT (n=21–42; P≤0.01). Upon resuming DOX (4wks after ET-1 induction and before HF has developed), subsequent structural and functional remodeling was abrogated. Of interest, expression and phosphorylation of gap junction protein Cx43 was decreased in BT but not NBT mice as early as 4 wks after ET-1 induction, and also reversible upon the restoration of DOX.
Conclusion: In this model, ET-1-induced cardiac electrical abnormalities and gap junction disruption (4wk) preceded LV dysfunction (6–8 wk). Preventing HF by reintroducing DOX 4 wks after its withdrawal suggests strongly that a primary electrical abnormality plays a role in subsequent LV dysfunction.