Patel R, Nagueh S F, Tsybouleva N, Abdellatif M, Lutucuta S, Kopelen H A, Quinones M A, Zoghbi W A, Entman M L, Roberts R, Marian A J
Section of Cardiology, Department of Medicine, The DeBakey Heart Center, The Methodist Hospital and Baylor College of Medicine, Houston, Texas, USA.
Circulation. 2001 Jul 17;104(3):317-24. doi: 10.1161/hc2801.094031.
Hypertrophic cardiomyopathy is a genetic disease characterized by cardiac hypertrophy, myocyte disarray, interstitial fibrosis, and left ventricular (LV) dysfunction. We have proposed that hypertrophy and fibrosis, the major determinants of mortality and morbidity, are potentially reversible. We tested this hypothesis in beta-myosin heavy chain-Q(403) transgenic rabbits.
We randomized 24 beta-myosin heavy chain-Q(403) rabbits to treatment with either a placebo or simvastatin (5 mg. kg(-1). d(-1)) for 12 weeks and included 12 nontransgenic controls. We performed 2D and Doppler echocardiography and tissue Doppler imaging before and after treatment. Demographic data were similar among the groups. Baseline mean LV mass and interventricular septal thickness in nontransgenic, placebo, and simvastatin groups were 3.9+/-0.7, 6.2+/-2.0, and 7.5+/-2.1 g (P<0.001) and 2.2+/-0.2, 3.1+/-0.5, and 3.3+/-0.5 mm (P=0.002), respectively. Simvastatin reduced LV mass by 37%, interventricular septal thickness by 21%, and posterior wall thickness by 13%. Doppler indices of LV filling pressure were improved. Collagen volume fraction was reduced by 44% (P<0.001). Disarray was unchanged. Levels of activated extracellular signal-regulated kinase (ERK) 1/2 were increased in the placebo group and were less than normal in the simvastatin group. Levels of activated and total p38, Jun N-terminal kinase, p70S6 kinase, Ras, Rac, and RhoA and the membrane association of Ras, RhoA, and Rac1 were unchanged.
Simvastatin induced the regression of hypertrophy and fibrosis, improved cardiac function, and reduced ERK1/2 activity in the beta-myosin heavy chain-Q(403) rabbits. These findings highlight the need for clinical trials to determine the effects of simvastatin on cardiac hypertrophy, fibrosis, and dysfunction in humans with hypertrophic cardiomyopathy and heart failure.
肥厚型心肌病是一种遗传性疾病，其特征为心肌肥厚、心肌细胞排列紊乱、间质纤维化以及左心室（LV）功能障碍。我们提出，肥厚和纤维化作为死亡率和发病率的主要决定因素，可能是可逆的。我们在β-肌球蛋白重链-Q(403)转基因兔中验证了这一假设。
我们将24只β-肌球蛋白重链-Q(403)兔随机分为两组，分别给予安慰剂或辛伐他汀（5毫克·千克⁻¹·天⁻¹）治疗12周，并纳入12只非转基因对照兔。在治疗前后进行二维和多普勒超声心动图以及组织多普勒成像检查。各组间人口统计学数据相似。非转基因组、安慰剂组和辛伐他汀组的基线平均左心室质量和室间隔厚度分别为3.9±0.7、6.2±2.0和7.5±2.1克（P<0.001）以及2.2±0.2、3.1±0.5和3.3±0.5毫米（P=0.002）。辛伐他汀使左心室质量减少37%，室间隔厚度减少21%，后壁厚度减少13%。左心室充盈压的多普勒指标得到改善。胶原容积分数降低了44%（P<0.001）。排列紊乱情况未改变。安慰剂组中活化的细胞外信号调节激酶（ERK）1/2水平升高，而辛伐他汀组低于正常水平。活化的和总的p38、Jun N端激酶、p70S6激酶、Ras、Rac和RhoA水平以及Ras、RhoA和Rac1的膜结合情况未改变。
辛伐他汀可使β-肌球蛋白重链-Q(403)兔的肥厚和纤维化消退，改善心脏功能，并降低ERK1/2活性。这些发现凸显了开展临床试验以确定辛伐他汀对肥厚型心肌病和心力衰竭患者的心脏肥厚、纤维化及功能障碍影响的必要性。
