McDonald K M, Garr M, Carlyle P F, Francis G S, Hauer K, Hunter D W, Parish T, Stillman A, Cohn J N
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455.
Circulation. 1994 Dec;90(6):3034-46. doi: 10.1161/01.cir.90.6.3034.
Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock.
The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 +/- 3.4 to 65.4 +/- 2.6 g, P = NS; LVV, 45.4 +/- 2.7 to 51.6 +/- 2.7 mL, P = NS; C: LVM, 68.4 +/- 3.2 to 91.4 +/- 2.9 g, P = .0001; LVV, 56.6 +/- 3.0 to 71.9 +/- 2.4 mL, P = .0003). Terazosin, an alpha 1-adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 +/- 4.6 to 105.7 +/- 3.4 g, P = .01; LVV, 61.8 +/- 3.8 to 76.8 +/- 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 +/- 4.6 to 109.7 +/- 5.3 g, P = .0001; LVV, 66.0 +/- 1.9 to 78.4 +/- 3.6 mL, P = .007).
High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. the failure of alpha 1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha 1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.
心肌损伤后进行性心室重构与预后不良相关。要对重构过程中涉及的组织病理学过程进行最佳预防，需要更全面地了解启动和维持这些结构变化的机制。由于交感神经系统和肾素 - 血管紧张素系统可能参与重构过程，因此在经心肌直流电休克导致局部心肌损伤的犬模型中评估了药物抑制剂的结构效应。
该研究由两个连续进行的方案组成。在方案1中，转换酶抑制剂（CEI）佐芬普利（Z）可预防对照组（C）在16周时出现的左心室质量（LVM）和舒张末期容积（LVV）增加（Z组：LVM，从69.8±3.4 g降至65.4±2.6 g，P =无显著性差异；LVV，从45.4±2.7 mL增至51.6±2.7 mL，P =无显著性差异；C组：LVM，从68.4±3.2 g增至91.4±2.9 g，P = 0.0001；LVV，从56.6±3.0 mL增至71.9±2.4 mL，P = 0.0003）。α1肾上腺素能受体拮抗剂特拉唑嗪尽管持续存在受体阻断作用，但在16周时未能预防重构。在方案2中，证实了雷米普利全剂量CEI治疗的抗重构作用。低剂量雷米普利未产生血流动力学效应，未能预防重构（LVM，从89.7±4.6 g增至105.7±3.4 g，P = 0.01；LVV，从61.8±3.8 mL增至76.8±3.3 mL，P = 0.002）。血管紧张素II 1型受体阻滞剂也未能预防LVM或LVV的增加（LVM，从89.0±4.6 g增至109.7±5.3 g，P = 0.0001；LVV，从66.0±1.9 mL增至78.4±3.6 mL，P = 0.007）。
高剂量CEI治疗可预防直流电休克所致局部心肌损伤引起的进行性结构变化。α1肾上腺素能受体阻断和血管紧张素II 1型阻断未能减轻重构，这表明在该模型的重构过程中，去甲肾上腺素通过α1受体起作用或血管紧张素II通过1型受体起作用并不起重要的直接作用。
