权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

DYNAMIC CARDIOMYOPLASTY

动态心肌成形术

基本信息

批准号：
6389888
负责人：
WILLIAM P SANTAMORE
金额：
$ 43.75万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2003-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6389888
关键词：
blood pressure blood volume dogs fibroblast growth factor heart circulation heart failure heart function heart rate heart revascularization heart surgery heart ventricle immunocytochemistry microcapsule myocardium nonhuman therapy evaluation vascular endothelial growth factors

项目摘要

Cardiomyoplasty (CMP), a surgical treatment for heart failure, has several advantages: skeletal muscle requires no external power source; each patient serves as his/her "donor;" and rejection is not a problem. CMP prevents systolic bulging and inhibits progressive ventricular enlargement. Both mechanisms probably contribute to subjective decrease in symptoms and may explain phase II clinical CMP trials, in which, progressive left ventricular (LV) enlargement was inhibited. However, experimentally and clinically, systolic augmentation of LV function by latissimus dorsi muscle (LDM) is rarely observed. This is a major problem. Our view is that CMP will not thrive as a viable approach without physiologically important large increases in LV pressure and outflow with LDM stimulation. Our goal is to achieve these large pressure and flow increases. Our approach is to systematically examine this problem by sequentially measuring the effects of different interventions. Typically, CMP studies try some intervention, and only examine the effects after LDM training. We believe that this has been a major mistake, and has actually slowed progress. Important improvements may have been missed. Our approach is to maximize the response at 2 weeks after surgery (already accomplished). Then from this foundation, obtain the best results at 1, 2, and 3 months. This grant will examine preconditioning (for revascularization) and daily rest periods (intermittent stimulation). Our aims are for little, if any, LDM damage and a strong, yet fatigue resistant, muscle. With this muscle, LDM stimulation should increase LV pressure by 15 to 20 mmHg and stroke volume by 20 to 30 percent. We will test these interventions in 2 sections. In both, LV function will be depressed by intra-coronary microsphere injections. In preconditioning studies, vascular delay (dividing part of vascular supply prior to surgery) and/or injections of bFGF will be tested to stimulate revascularization and decrease LDM damage. Dogs will be randomly divided into control, standard CMP, CMP with vascular delay, and CMP with vascular delay plus bFGF groups. Revascularization will be assessed histologically and by measuring regional LDM blood flow and vascular growth factors. At 2 weeks, 1, 2, and 3 months, LV function will be assessed. In intermittent stimulation studies, after preconditioning, dogs will be randomly divided into continuous (24 hours/day) vs intermittent LDM stimulation groups (stimulator off 8 hrs/day). At 2 weeks, 1, 2, and 3 months, LV function will be assessed. The mechanisms will be examined by immuno-histochemical techniques and by experiments to assess LDM mechanical performance. In preliminary experiments, the results have reached our goals: 19 mmHg increases in peak LV pressure and 40 percent increases in stroke volume. These very large increases are consistent with our hypothesis and show that significant increases in LV pressure and stroke volume can occur with LDM stimulation.

心肌成形术（CMP）是一种治疗心力衰竭的外科手术，具有以下几个优点：骨骼肌不需要外部动力源；每个病人都是他/她的“捐赠者”；拒绝不是问题。 CMP 可防止收缩期膨出并抑制进行性心室扩大。这两种机制可能有助于主观症状的减轻，并可能解释 II 期临床 CMP 试验，其中进展性左心室 (LV) 扩大受到抑制。然而，在实验和临床上，很少观察到背阔肌（LDM）对左室功能的收缩增强。这是一个大问题。我们的观点是，如果 LDM 刺激下左心室压力和流出量没有生理上重要的大幅增加，CMP 就不会成为一种可行的方法。我们的目标是实现压力和流量的大幅增加。我们的方法是通过依次测量不同干预措施的效果来系统地研究这个问题。通常，CMP 研究会尝试一些干预措施，并且仅检查 LDM 培训后的效果。我们认为这是一个重大错误，并且实际上减缓了进展。重要的改进可能已被错过。我们的方法是在手术后两周最大化反应（已经完成）。然后以此为基础，在1、2、3个月时获得最佳效果。这笔拨款将检查预处理（用于血运重建）和每日休息时间（间歇性刺激）。我们的目标是尽量减少 LDM 损伤（如果有的话），并打造强健且抗疲劳的肌肉。对于这块肌肉，LDM 刺激应使 LV 压力增加 15 至 20 mmHg，每搏输出量增加 20% 至 30%。我们将分两部分测试这些干预措施。在这两种情况下，冠状动脉内微球注射都会抑制左心室功能。在预处理研究中，将测试血管延迟（在手术前分割部分血管供应）和/或注射 bFGF 以刺激血运重建并减少 LDM 损伤。将犬随机分为对照组、标准 CMP、血管延迟 CMP 和血管延迟加 bFGF 的 CMP 组。血运重建将通过组织学和测量局部 LDM 血流量和血管生长因子进行评估。在 2 周、1、2 和 3 个月时，将评估左心室功能。在间歇性刺激研究中，预处理后，狗将被随机分为连续（24 小时/天）和间歇性 LDM 刺激组（刺激器关闭 8 小时/天）。在 2 周、1、2 和 3 个月时，将评估左心室功能。将通过免疫组织化学技术和评估 LDM 机械性能的实验来检查这些机制。在初步实验中，结果达到了我们的目标：左心室峰值压力增加 19 mmHg，每搏输出量增加 40%。这些非常大的增加与我们的假设一致，并表明 LDM 刺激可导致左心室压力和每搏输出量显着增加。