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首页> 外文期刊>Journal of Cardiovascular Development and Disease >Targeted Mybpc3 Knock-Out Mice with Cardiac Hypertrophy Exhibit Structural Mitral Valve Abnormalities
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Targeted Mybpc3 Knock-Out Mice with Cardiac Hypertrophy Exhibit Structural Mitral Valve Abnormalities

机译：心肌肥大的靶向Mybpc3基因敲除小鼠表现出结构性二尖瓣异常。

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MYBPC3 mutations cause hypertrophic cardiomyopathy, which is frequently associated with mitral valve (MV) pathology. We reasoned that increased MV size is caused by localized growth factors with paracrine effects. We used high-resolution echocardiography to compare Mybpc3-null, heterozygous, and wild-type mice (n = 84, aged 3–6 months) and micro-CT for MV volume (n = 6, age 6 months). Mybpc3-null mice showed left ventricular hypertrophy, dilation, and systolic dysfunction compared to heterozygous and wild-type mice, but no systolic anterior motion of the MV or left ventricular outflow obstruction. Compared to wild-type mice, echocardiographic anterior leaflet length (adjusted for left ventricular size) was greatest in Mybpc3-null mice (1.92 ± 0.08 vs. 1.72 ± 0.08 mm, p 0.001), as was combined leaflet thickness (0.23 ± 0.04 vs. 0.15 ± 0.02 mm, p 0.001). Micro-CT analyses of Mybpc3-null mice demonstrated increased MV volume (0.47 ± 0.06 vs. 0.15 ± 0.06 mm3, p = 0.018) and thickness (0.35 ± 0.04 vs. 0.12 ± 0.04 mm, p = 0.002), coincident with increased markers of TGFβ activity compared to heterozygous and wild-type littermates. Similarly, excised MV from a patient with MYBPC3 mutation showed increased TGFβ activity. We conclude that MYBPC3 deficiency causes hypertrophic cardiomyopathy with increased MV leaflet length and thickness despite the absence of left ventricular outflow-tract obstruction, in parallel with increased TGFβ activity. MV changes in hypertrophic cardiomyopathy may be due to paracrine effects, which represent targets for therapeutic studies.
机译：MYBPC3突变引起肥厚型心肌病，这通常与二尖瓣（MV）病理相关。我们认为增加的MV大小是由具有旁分泌作用的局部生长因子引起的。我们使用高分辨率超声心动图比较了Mybpc3-null，杂合和野生型小鼠（n = 84，年龄3–6个月）和micro-CT的MV体积（n = 6，年龄6个月）。与杂合型和野生型小鼠相比，Mybpc3-null小鼠显示左心室肥大，扩张和收缩功能障碍，但MV的收缩前运动或左心室流出道梗阻均没有。与野生型小鼠相比，在Mybpc3型小鼠中，超声心动图前小叶长度（针对左心室大小进行了调整）最大（1.92±0.08对1.72±0.08 mm，p <0.001），以及小叶总厚度（0.23±0.04）相对于0.15±0.02毫米，p <0.001）。对Mybpc3-null小鼠的Micro-CT分析显示增加的MV体积（0.47±0.06 vs. 0.15±0.06 mm 3 ，p = 0.018）和厚度增加（0.35±0.04 vs. 0.12±0.04 mm，p = 0.002），与杂合子和野生型同窝仔相比，TGFβ活性的标记物增加。同样，从患有MYBPC3突变的患者中切除的MV显示TGFβ活性增加。我们的结论是，尽管缺乏左心室流出道梗阻，MYBPC3缺乏会导致肥厚型心肌病，MV小叶长度和厚度增加，同时TGFβ活性增加。肥厚型心肌病的MV变化可能归因于旁分泌作用，这代表了治疗研究的目标。

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