MYK-461

MYK - 461
  • 文章类型: Journal Article
    暂无摘要。
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    这项荟萃分析是为了评估mavacamten在肥厚型心肌病患者中的疗效和安全性。
    使用PubMed进行了搜索,科克伦,和Scopus截至2022年8月的随机研究报告我们预先指定的结果。
    观察到mavacamten显着改善了纽约心脏协会等级(p<0.009),堪萨斯城心肌病问卷的临床总结评分(p=0.02),运动后左心室流出道梯度(p<0.00001),功能终点(p=0.05),并降低了中隔减少治疗率(p<0.00001)。然而,≥1次严重不良事件无显著差异,≥1例治疗引起的不良事件,左心室容积指数,左心室充盈压,左心室舒张末期容积指数,和峰值摄氧量(pVO2)。
    需要进行未来的大规模试验,以确认我们的结果,并确定在这些患者中使用mavacampen的长期益处和风险。
    Mavacamten是最近推出的一种放松心肌的药物,适用于肥厚型心肌病(一种心脏部分变厚变硬的疾病)患者。为了确定这种药物的有效性和安全性,将临床试验的结果合并以得出总体估计.总的来说,观察到mavacampen改善了与心脏相关的大多数功能参数,并且没有显示副作用数量的显着增加。这表明mavacampen的有效性和安全性,尽管需要进一步的试验来证实我们的结果.
    UNASSIGNED: This meta-analysis was performed to assess the efficacy and safety of mavacamten in patients with hypertrophic cardiomyopathy.
    UNASSIGNED: A search was conducted using PubMed, Cochrane, and Scopus up to August 2022 for randomized studies reporting our pre-specified outcomes.
    UNASSIGNED: It was observed that mavacamten significantly improved New York Heart Association class (p < 0.009), Clinical Summary Score of the Kansas City Cardiomyopathy Questionnaire (p = 0.02), post-exercise left ventricular outflow tract gradient (p < 0.00001), functional end point (p = 0.05), and lowered septal reduction therapy rates (p < 0.00001). However, there were no significant differences in the ≥1 severe adverse events, ≥1 treatment-emergent adverse events, left ventricular volume index, left ventricular filling pressure, left ventricular end-diastolic volume index, and peak oxygen uptake (pVO2).
    UNASSIGNED: Future large-scale trials are required to confirm our results and determine the long-term benefits and risks of mavacamten use in these patients.
    Mavacamten is a recently introduced medication that relaxes the heart muscle and is indicated for patients with hypertrophic cardiomyopathy (a disease in which parts of the heart become thick and stiff). To determine the effectiveness and safety of this drug, the results of clinical trials were combined in order to produce an overall estimate. Overall, it was observed that mavacamten improved most functional parameters related to the heart and demonstrated no significant increases in the number of side effects. This suggests the effectiveness and safety of mavacamten, although further trials are needed to confirm our results.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    暂无摘要。
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    人类诱导多能干细胞衍生的心肌细胞(hiPSC-CM)与CRISPR/Cas9基因组编辑相结合,为研究心脏生物学和疾病提供了无与伦比的机会。然而,肉瘤,肌细胞收缩的基本单位,在HiPSC-CM中是不成熟和非线性的,这在技术上挑战了对搏动细胞收缩参数的准确功能询问。此外,现有的分析方法吞吐量相对较低,间接评估收缩性,或仅评估在成熟的心脏组织中发现的对齐良好的肉瘤。
    我们的目标是开发一个分析平台,迅速,并自动跟踪搏动心肌细胞中的肉瘤。该平台应该评估sarcomere内容,收缩和松弛参数,和节拍率。
    我们开发了SarcTrack,aMatLab软件,用于监控hiPSC-CM中荧光标记的sarcome。该算法确定sarcome含量,肌节长度,以及肌节收缩和松弛的回报率。通过快速测量每个hiPSC-CM中的数百个肉瘤,SarcTrack为多个收缩参数的强大统计分析提供了大量数据集。我们通过分析药物治疗的hiPSC-CM来验证SarcTrack,确认直接激活(CK-1827452)或抑制(MYK-461)肌球蛋白分子或间接改变收缩性(维拉帕米和普萘洛尔)的化合物的收缩作用。在肌球蛋白结合蛋白C(MYBPC3)基因中携带杂合截短变体的hiPSC-CM的SarcTrack分析,导致肥厚型心肌病,概述了精液疾病的表型,包括心脏收缩过度和松弛减少,用MYK-461治疗恢复正常的异常。
    SarcTrack提供了一种直接有效的方法来定量评估肌节功能。通过改进现有的收缩性分析方法并克服与hiPSC-CM功能评估相关的技术挑战,SarcTrack增强了肌节调节疗法的翻译前景,并加速了人类心脏遗传变异的询问。
    Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in combination with CRISPR/Cas9 genome editing provide unparalleled opportunities to study cardiac biology and disease. However, sarcomeres, the fundamental units of myocyte contraction, are immature and nonlinear in hiPSC-CMs, which technically challenge accurate functional interrogation of contractile parameters in beating cells. Furthermore, existing analysis methods are relatively low-throughput, indirectly assess contractility, or only assess well-aligned sarcomeres found in mature cardiac tissues.
    We aimed to develop an analysis platform that directly, rapidly, and automatically tracks sarcomeres in beating cardiomyocytes. The platform should assess sarcomere content, contraction and relaxation parameters, and beat rate.
    We developed SarcTrack, a MatLab software that monitors fluorescently tagged sarcomeres in hiPSC-CMs. The algorithm determines sarcomere content, sarcomere length, and returns rates of sarcomere contraction and relaxation. By rapid measurement of hundreds of sarcomeres in each hiPSC-CM, SarcTrack provides large data sets for robust statistical analyses of multiple contractile parameters. We validated SarcTrack by analyzing drug-treated hiPSC-CMs, confirming the contractility effects of compounds that directly activate (CK-1827452) or inhibit (MYK-461) myosin molecules or indirectly alter contractility (verapamil and propranolol). SarcTrack analysis of hiPSC-CMs carrying a heterozygous truncation variant in the myosin-binding protein C ( MYBPC3) gene, which causes hypertrophic cardiomyopathy, recapitulated seminal disease phenotypes including cardiac hypercontractility and diminished relaxation, abnormalities that normalized with MYK-461 treatment.
    SarcTrack provides a direct and efficient method to quantitatively assess sarcomere function. By improving existing contractility analysis methods and overcoming technical challenges associated with functional evaluation of hiPSC-CMs, SarcTrack enhances translational prospects for sarcomere-regulating therapeutics and accelerates interrogation of human cardiac genetic variants.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    Mavacamten,以前被称为MYK-461是最近发现的一种新的心肌肌球蛋白小分子调节剂,靶向肥厚型心肌病潜在的肌节过度收缩,最普遍的遗传性心血管疾病之一。对分离的细胞和肌纤维以及完整动物的研究表明,mavacamten抑制肌节力的产生,从而降低心脏收缩力。最初的机理研究表明,mavacamten主要通过抑制β-心肌肌球蛋白S1的磷酸盐释放速率来降低稳态ATPase活性,但尚未描述mavacamten的分子作用机制。在这里,我们使用稳态和预稳态动力学分析来研究mavacampen的作用机理。瞬态动力学分析显示,mavacamten调节肌球蛋白化学机械循环的多个步骤。除了减少循环的限速步骤(磷酸盐释放)之外,mavacamten减少了从弱结合状态过渡到强结合状态期间可以与肌动蛋白细丝相互作用的肌球蛋白S1头部的数量,而不会影响固有速率。Mavacamten还降低了肌球蛋白在ADP结合状态下与肌动蛋白结合的速率以及单独的肌球蛋白S1的ADP释放速率。我们,因此,得出的结论是,mavacten作用于肌球蛋白化学机械周期的多个阶段。尽管mavacamten介导的抑制心肌肌球蛋白的主要机制是减少β-心肌肌球蛋白S1的磷酸盐释放,但次要机制减少了从弱结合状态过渡到强结合状态的肌动蛋白结合头的数量,这发生在磷酸盐释放之前,并且可以提供调节肌球蛋白功能的另一种方法。
    Mavacamten, formerly known as MYK-461 is a recently discovered novel small-molecule modulator of cardiac myosin that targets the underlying sarcomere hypercontractility of hypertrophic cardiomyopathy, one of the most prevalent heritable cardiovascular disorders. Studies on isolated cells and muscle fibers as well as intact animals have shown that mavacamten inhibits sarcomere force production, thereby reducing cardiac contractility. Initial mechanistic studies have suggested that mavacamten primarily reduces the steady-state ATPase activity by inhibiting the rate of phosphate release of β-cardiac myosin-S1, but the molecular mechanism of action of mavacamten has not been described. Here we used steady-state and presteady-state kinetic analyses to investigate the mechanism of action of mavacamten. Transient kinetic analyses revealed that mavacamten modulates multiple steps of the myosin chemomechanical cycle. In addition to decreasing the rate-limiting step of the cycle (phosphate release), mavacamten reduced the number of myosin-S1 heads that can interact with the actin thin filament during transition from the weakly to the strongly bound state without affecting the intrinsic rate. Mavacamten also decreased the rate of myosin binding to actin in the ADP-bound state and the ADP-release rate from myosin-S1 alone. We, therefore, conclude that mavacamten acts on multiple stages of the myosin chemomechanical cycle. Although the primary mechanism of mavacamten-mediated inhibition of cardiac myosin is the decrease of phosphate release from β-cardiac myosin-S1, a secondary mechanism decreases the number of actin-binding heads transitioning from the weakly to the strongly bound state, which occurs before phosphate release and may provide an additional method to modulate myosin function.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Sci-hub)

公众号