BETA BLOCKADE IN MITRAL REGURGITATION

二尖瓣反流(MR)对左心室造成容量超负荷。 最终导致左心功能不全。这样的功能障碍 与随后的发病率和手术死亡率增加有关。 在最初的资金支持期间，我们发生了闭合性胸膜脊索破裂。 严重MR的模型，其后果不可避免地向左 心功能不全。因此，我们开发了一个工具来检查 使用此工具的MR中左心功能不全的原因： 1)我们发现在体左心功能不全密切相关 从受影响的脑室分离的肌细胞功能障碍 这反过来又与肌细胞肌原纤维的丧失有关。 2)令人兴奋的是，我们发现心肌细胞和心功能不全 如果用二尖瓣纠正反流是可逆的 替补。 已经确定MR患者的左心功能不全是可逆的 肌原纤维丢失所致的肌细胞特性，然后我们寻找特定的 细胞功能障碍发生的机制。先导研究 这一提议的基础表明，在MR中，β-受体阻滞剂 导致两组左心功能不全显著改善 和肌细胞功能障碍，肌原纤维密度恢复到 正常水平。这些数据表明，β-肾上腺素能过度刺激 实验性MR心功能不全的原因之一 目前的建议，我们将完成这些初步研究，并巩固这一点 前提。一旦确定了这一点，我们将解决三个具体的问题 β-肾上腺素能过度刺激可能导致 功能障碍： 1)心动过速在功能障碍时发生，并随着 β-受体阻滞剂是或不是β受体的负面影响的原因 过度刺激和β-受体阻滞剂的积极作用。 2)尽管β-受体上调发生在β-受体阻断和 可能在左心室对应激的反应中起重要作用 β-受体阻滞剂改善收缩功能的机制是 增强的先天收缩功能。我们将通过以下方式验证这一假设 检测大鼠心肌细胞收缩功能的变化 无肾上腺素能刺激的制剂。 3)我们将确定增加的肌原纤维密度是否必须 对测试版之后看到的改进负有部分责任- 肾上腺素能阻断是由β-受体阻滞剂诱导的蛋白质增加引起的 蛋白质合成或降解减少。

Mitral regurgitation (MR) imposes a volume overload on the left ventricle which eventually leads to left ventricular dysfunction. Such dysfunction is associated with subsequent morbidity and increased operative mortality. In the initial funding period, we developed a closed-chest chordal rupture model of severe MR, the consequence of which was inevitable left ventricular dysfunction. Thus, we have developed a tool to examine the causes of left ventricular dysfunction in MR. Using this tool: 1) We found that in vivo left ventricular dysfunction correlated closely with the dysfunction of myocytes isolated from the affected ventricle which in turn correlated with the loss of myocyte myofibrils. 2) Excitingly, we found that both the myocyte and ventricular dysfunction were reversible if the regurgitation was corrected by mitral valve replacement. Having defined that left ventricular dysfunction in MR was a reversible property of the myocyte due to myofibrillar loss, we then sought specific mechanisms by which the cell dysfunction occurred. Pilot studies which form the basis of this proposal demonstrated that beta-blockade in MR resulted in striking improvement of both the left ventricular dysfunction and myocyte dysfunction with a return of myofibrillar density toward normal levels. These data suggest that beta-adrenergic overstimulation is one cause of the ventricular dysfunction in experimental MR. In the current proposal, we will complete these pilot studies and cement this premise. Once this is established, we will then address three specific mechanisms by which beta-adrenergic overstimulation could be causing the dysfunction: 1) That tachycardia which occurs with dysfunction and is reduced with beta-blockade is or is not the cause of the negative effects of beta overstimulation and the positive effects of beta-blockade. 2) That although beta-receptor up-regulation occurs with beta-blockade and may be important in the left ventricular response to stress, the primary mechanism by which contractile function is improved by beta-blockade is enhanced innate contractile function. We will test this hypothesis by examining changes in isolated myocyte contractile function in a preparation devoid of adrenergic stimulation. 3) We will determine whether the increased myofibrillar density which must be in part responsible for the improvement seen following a beta- adrenergic blockade is due to a beta-blocker-induced increase in protein synthesis or a decrease in protein degradation.