UNASSIGNED: We treated male LmnaH222P/H222P mice, after the onset of heart failure, with placebo or either of 2 orally bioavailable mTOR inhibitors: everolimus or NV-20494, a rapamycin analog highly selective against mTORC1. We examined left ventricular remodeling, and the cell biological, biochemical, and histopathologic features of cardiomyopathy, potential drug toxicity, and survival.
UNASSIGNED: Everolimus treatment (n=17) significantly reduced left ventricular dilatation and increased contractility on echocardiography, with a 7% (P=0.018) reduction in left ventricular end-diastolic diameter and a 39% (P=0.0159) increase fractional shortening compared with placebo (n=17) after 6 weeks of treatment. NV-20494 treatment (n=15) yielded similar but more modest and nonsignificant changes. Neither drug prevented the development of cardiac fibrosis. Drug treatment reactivated suppressed autophagy and inhibited mTORC1 signaling in the heart, although everolimus was more potent. With regards to drug toxicity, everolimus alone led to a modest degree of glucose intolerance during glucose challenge. Everolimus (n=20) and NV-20494 (n=20) significantly prolonged median survival in LmnaH222P/H222P mice, by 9% (P=0.0348) and 11% (P=0.0206), respectively, compared with placebo (n=20).
UNASSIGNED: These results suggest that mTOR inhibitors may be beneficial in patients with cardiomyopathy caused by LMNA mutations and that further study is warranted.
■我们治疗了雄性LmnaH222P/H222P小鼠,心力衰竭发作后,安慰剂或2种口服生物可利用的mTOR抑制剂:依维莫司或NV-20494,一种对mTORC1具有高度选择性的雷帕霉素类似物。我们检查了左心室重构,和细胞生物学,生物化学,和心肌病的组织病理学特征,潜在的药物毒性,和生存。
■依维莫司治疗(n=17)可显着减少左心室扩张并增加超声心动图的收缩力,治疗6周后,与安慰剂组(n=17)相比,左心室舒张末期内径减少7%(P=0.018),缩短率增加39%(P=0.0159)。NV-20494治疗(n=15)产生了相似但更温和和不显著的变化。两种药物都不能阻止心脏纤维化的发展。药物治疗重新激活抑制自噬和抑制mTORC1信号在心脏,尽管依维莫司更有效。关于药物毒性,在葡萄糖挑战期间,仅依维莫司导致适度的葡萄糖耐受不良。依维莫司(n=20)和NV-20494(n=20)显著延长LmnaH222P/H222P小鼠的中位生存期,9%(P=0.0348)和11%(P=0.0206),分别,与安慰剂相比(n=20)。
■这些结果表明,mTOR抑制剂可能对LMNA突变引起的心肌病患者有益,需要进一步研究。