BETA BLOCKADE IN MITRAL REGURGITATION

β 阻断治疗二尖瓣反流

• 批准号: 2028292
• 负责人: BLASE A CARABELLO
• 金额: $ 17.05万
• 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/2028292
• 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）在左心室施加了体积超负荷 最终导致左心室功能障碍。这种功能障碍 与随后的发病率和手术死亡率增加有关。 在最初的资金期间，我们开发了一个闭合的和弦破裂 严重MR的模型，其结果不可避免 心室功能障碍。因此，我们开发了一个工具来检查 MR中左心室功能障碍的原因。使用此工具： 1）我们发现体内左心功能障碍密切相关 从受影响的心室分离的肌细胞功能障碍 这反过来与肌细胞肌原纤维的丧失有关。 2）令人兴奋的是，我们发现肌细胞和心室功能障碍 如果通过二尖瓣校正了反流，则可逆 替代品。 在MR中定义了左心功能障碍是可逆的 由于肌原纤维损失，肌细胞的特性，然后我们寻求特定 细胞功能障碍发生的机制。试点研究 构成该提案的基础表明MR中的β受体阻滞 导致左心室功能障碍的显着改善 和心肌功能障碍，肌原纤维密度返回 正常水平。这些数据表明β-肾上腺素能过度刺激是 实验MR中心室功能障碍的原因之一。在 当前的建议，我们将完成这些试点研究并巩固这一点 前提。一旦建立了这一点，我们将解决三个特定的 β-肾上腺素能过度刺激可能导致的机制 功能障碍： 1）患有功能障碍的心动过速，并减少 Beta-Blockade是beta的负面影响的原因或不是 过度刺激和β受体阻滞的积极影响。 2）尽管β受体上调发生在Beta-Blockade和 在左心室对压力的反应中可能很重要 通过Beta-Blockade提高收缩功能的机制为 增强的先天收缩功能。我们将通过 检查孤立的心肌收缩功能的变化 没有肾上腺素能刺激的制剂。 3）我们将确定是否必须增加肌原纤维密度 部分负责β- 肾上腺素能阻断是由于β受体阻滞剂引起的蛋白质增加 合成或蛋白质降解的降低。

项目成果

Left ventricular mechanics and myocyte function after correction of experimental chronic mitral regurgitation by combined mitral valve replacement and preservation of the native mitral valve apparatus.

通过联合二尖瓣置换术和保留原生二尖瓣装置纠正实验性慢性二尖瓣反流后的左心室力学和肌细胞功能。

• 发表时间: 1992
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Ishihara,K;Zile,MR;Kanazawa,S;Tsutsui,H;Urabe,Y;DeFreyte,G;Carabello,BA
• 通讯作者: Carabello,BA

Anesthetic and postoperative protocols for a canine model of reversible left ventricular volume overload.

可逆性左心室容量超负荷犬模型的麻醉和术后方案。

• DOI: 10.3109/08941939109141166
• 发表时间: 1991
• 期刊: Journal of investigative surgery : the official journal of the Academy of Surgical Research
• 作者: Swindle,MM;Spinale,FG;Smith,AC;Schumann,RE;Green,CT;Nakano,K;Kanasawa,S;Ishihara,K;Zile,MR;Carabello,BA
• 通讯作者: Carabello,BA