Transgenic α1A-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 alpha(1A)-adrenergic receptors (alpha(1A)-AR). We tested the hypothesis that this enhanced inotropy protects against dysfunction and remodeling after myocardial infarction (MI). Methods: We subjected alpha(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 alpha(1A)-TG groups (32 +/- 2 vs. 29 +/- 2% of LV, P=NS), mortality due to heart failure was lower after M1 in the alpha(1A)-TG (37%, n=39) than that in the NTG animals (63%, n=56, P=0.026). NTG and alpha(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 alpha(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 alpha(1A)-TG vs. NTG mice (7270 +/- 324, vs. 5938 +/- 372 mmHg/s, P < 0.05). Conclusion: Enhanced inotropy resulting from transgenic overexpression of alpha(1A)-AR is well maintained chronically after MI and limits echocardiography-determined LV remodeling, preserves function, and reduces acute heart failure death. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.