BETA BLOCKADE IN MITRAL REGURGITATION

β 阻断治疗二尖瓣反流

• 批准号: 2218731
• 负责人: BLASE A CARABELLO
• 金额: $ 13.9万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2218731
• 关键词: atenolol; beta adrenergic agent; beta antiadrenergic agent; catecholamines; cineangiocardiography; congestive heart failure; disease /disorder model; dogs; heart circulation; heart contraction; intracardiac volume; mitral valve insufficiency; myofibrils; prosthetic heart valve

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.

二尖瓣反流 (MR) 导致左心室容量超负荷 最终导致左心室功能障碍。这样的功能障碍 与随后的发病率和手术死亡率增加有关。 在最初的资助期间，我们开发了一种闭胸腱索断裂术 严重 MR 模型，其后果是不可避免的 left 心室功能障碍。因此，我们开发了一个工具来检查 MR 左心室功能不全的原因。使用这个工具： 1）我们发现体内左心室功能障碍密切相关 与受影响心室分离的肌细胞功能障碍 这反过来又与心肌细胞肌原纤维的损失相关。 2）令人兴奋的是，我们发现肌细胞和心室功能障碍 如果通过二尖瓣纠正反流，则可逆 替代品。 明确 MR 左心室功能障碍是可逆的 由于肌原纤维损失而改变了肌细胞的特性，然后我们寻求特定的 细胞功能障碍发生的机制。试点研究 该提案的基础表明 MR 中的 β 阻断 导致左心室功能障碍显着改善 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是 实验性 MR 中心室功能障碍的原因之一。在 目前的提案，我们将完成这些试点研究并巩固这一点 前提。一旦确定，我们将解决三个具体问题 β-肾上腺素能过度刺激可能导致的机制 功能障碍： 1) 心动过速随功能障碍而发生，并随功能障碍而减轻 β-阻断是或不是β负面影响的原因 过度刺激和β-阻断的积极作用。 2）虽然β受体上调发生在β受体阻滞剂和 可能在左心室对压力的反应中很重要，这是主要的 β-阻断改善收缩功能的机制是 增强先天收缩功能。我们将通过以下方式检验这个假设 检查离体心肌细胞收缩功能的变化 没有肾上腺素刺激的准备。 3) 我们将确定肌原纤维密度是否增加 对测试版后的改进负有部分责任- 肾上腺素能阻断是由于β-受体阻滞剂引起的蛋白质增加 合成或蛋白质降解减少。