Transgenic α_1A-adrenergic activation limits post-infarct ventricular remodeling and dysfunction and improves survival

Objective: Myocardial contractility is enhanced in transgenic (TG) mice with cardiac-restricted overexpression of the α_1A-adrenergic receptors (α_1A-AR). We tested the hypothesis that this enhanced inotropy protects against dysfunction and remodeling after myocardial infarction (MI). Methods: We subjected α_1A-TG and non-TG mice (NTG) to MI and determined changes in left ventricular (LV) function and diastolic dimension (LVDd) by echocardiography prior to and at 1, 3, 7, 12 and 15 weeks thereafter. Results: Although infarct size was similar in the NTG and α_1A-TG groups (32 ± 2 vs. 29 ± 2% of LV, P = NS), mortality due to heart failure was lower after MI in the α_1A-TG (37%, n = 39) than that in the NTG animals (63%, n = 56, P = 0.026). NTG and α_1A-TG mice showed similar reductions in LV fractional shortening (FS) and increases in LVDd at week-1 after MI. However, whereas NTG mice showed continuous deterioration over a 15-week period after MI in FS (fell by 40%, from 30 ± 2 to 18 ± 1%, P < 0.01) and LVDd (increased by 24%, from 4.2 ± 0.1 to 5.2 ± 0.1 mm, P < 0.01), the changes in both FS (fell by 14%, from 42 ± 2 to 36 ± 2%) and LVDd (increased by 8%, from 3.8 ± 0.1 to 4.1 ± 0.1 mm, both changes P < 0.01 vs. NTG) were significantly less severe in the α_1A-TG mice and did not progress after 3 weeks. At 15 weeks after MI, LV catheterization revealed better preservation of dP/dt_max in the α_1A-TG vs. NTG mice (7270 ± 324, vs. 5938 ± 372 mmHg/s, P < 0.05). Conclusion: Enhanced inotropy resulting from transgenic overexpression of α_1A-AR is well maintained chronically after MI and limits echocardiography-determined LV remodeling, preserves function, and reduces acute heart failure death.