Adding angiotensin II type 1 receptor blockade to angiotensin-converting enzyme inhibition limits myocyte remodeling after myocardial infarction

Abstract

Background: Adding angiotensin II type 1 receptor blockade (ARB) to angiotensin-converting enzyme inhibition (ACEI) further attenuates left ventricular (LV) remodeling in an ovine model of myocardial infarction (MI). We hypothesized that combined therapy with ACEI and ARB (CT) would be additive in the limitation of the myocyte hypertrophy and dysfunction that occurs in untreated adjacent noninfarcted regions during remodeling. Methods and Results: Nineteen sheep underwent coronary ligation to create a moderate-sized anteroapical infarction. Post-MI day 2, sheep were randomized to therapy with ramipril (ACEI, n = 5) or ramipril plus losartan (CT, n = 6) or none (untreated, n = 8). Infarct size was similar between groups. At 8 weeks post-MI, myocytes were isolated from regions adjacent to and remote from the infarct to measure morphometric indices (cell volume, length, cross-sectional area, width) and parameters of contraction (% shortening and −dL/dt, rate of shortening) and relaxation (+dL/dt [rate of relengthening] and TR 70% [time for 70% relengthening]). Volume % collagen was measured from adjacent and remote regions. Adjacent myocyte volume was different between groups (2.5 ± 0.1 × 104 μm3 in CT, 3.0 ± 0.4 × 104 μm3 in ACEI, 3.5 ± 0.2 × 104 μm3 in untreated, analysis of variance [ANOVA] P =.001) as was length (158 ± 4 μm, 161 ± 9 μm, 189 ± 8 μm, respectively, ANOVA P <.001). Adjacent cell volume and length in CT were lower than untreated (P <.05). Percent shortening and −dL/dt of isolated adjacent myocytes were improved with both ACEI (7.9 ± 0.3%, −131 ± 6 μm/sec, P <.05) and CT (7.7 ± 0.3%, −144 ± 8 μm/sec, P <.05) compared with no therapy (6.4 ± 0.4%, −104 ± 7 μm/sec), as was both +dL/dt and TR 70%. No between-group difference in volume % collagen was found in adjacent or remote regions. Conclusion: Compared with ACEI alone, the addition of ARB further limits adjacent noninfarcted myocyte hypertrophy during post-MI LV remodeling. Both ACEI alone and CT preserve isolated unloaded myocyte function, but neither significantly reduce interstitial collagen. The additional benefit of ARB on regional and global function in vivo may also be due to other factors including regional load.