Molecular Mechanisms of Volume Overload

容量超载的分子机制

基本信息

批准号：
7786058
负责人：
Louis Dell'ltalia
金额：
$ 55.89万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-15 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7786058
关键词：
3-Dimensional ANG gene Adrenergic Agents Adrenergic Receptor Angiotensin II Angiotensin-Converting Enzyme Inhibitors Aorta Aortic Valve Insufficiency Attenuated Biochemistry Blood specimen Canis familiaris Cardiac Cardiac Catheterization Procedures Cell Count Cells Cellular Structures Chronic Chymase Collagen Color Coronary Arteriosclerosis Coronary sinus structure Data Dilatation - action Disease Doppler Echocardiography Extracellular Matrix Extracellular Matrix Degradation Failure Fibrosis Functional disorder Growth Factor Heart Heart failure Inflammation Inflammatory Left Ventricular Remodeling Left atrial structure Link Magnetic Resonance Imaging Matrix Metalloproteinases Measurement Measures Mediating Mediator of activation protein Metalloproteases Mitral Valve Insufficiency Modeling Molecular Myocardial Myocardial tissue Myocardium Nature Nitric Oxide Operative Surgical Procedures Oxygen Patients Peptide Hydrolases Peripheral Pharmaceutical Preparations Placebos Plasma Process Production Randomized Renin-Angiotensin System Secondary to Severities Stress Sympathetic Nervous System Testing Therapeutic Time Tissues Tumor Necrosis Factor-alpha Vasodilation Vasodilator Agents activity marker adrenergic clinically relevant cytokine design hemodynamics human TNF protein improved indexing inflammatory marker leukocyte activation mast cell neural stimulation pressure prevent receptor repaired valve replacement

项目摘要

Mitral regurgitation (MR) creates a unique hemodynamic stress by inducing a low pressure form of volume overload due to ejection into the left atrium. Chronic therapy with vasodilators reduces LV wall stress and thereby delays the need for valve replacement in aortic regurgitation; however, no such data are currently available in patients with chronic MR using standard vasodilators or agents that block the RAS. In a clinically relevant dog model of MR, we have shown increased LV ACE and chymase expression, increased LV angiotensin II (ANG II) levels, and increased mast cell numbers, but as opposed to pressure overload, there was an absence of fibrosis with net extracellular matrix (ECM) degradation. 1-adrenergic receptor blockade but not ACE inhibitor or type-1 ANG (AT1) receptor blockade, attenuated ECM degradation and improved LV remodeling and function. Our preliminary studies show also that a mast cell stabilizing drug prevented ECM degradation and improved LV function. Furthermore, there is an association between the sympathetic nervous system and myocardial production of reactive inflammatory species. We hypothesize that sympathetic nervous system activation stimulates mast cell-mediated matrix metalloproteinase activation, ECM degradation, and progressive adverse LV remodeling and failure in volume overload of MR. In Aim 1, we will show the efficacy of 1-AR blockade over AT1 receptor blockade in patients with chronic, non-surgical MR of moderate severity. We will also test the hypothesis that improved LV remodeling due to 1-AR blockade relates to a reduction in plasma markers of inflammation and collagen turnover. In Aim 2, we will test the hypothesis that extent matrix metalloproteinase activation and reactive inflammatory species production in LV myocardium of patients with surgical MR relates to the extent of LV remodeling defined by 3-dimensional magnetic resonance imaging and tissue tagging. In Aim 3, we will test the hypothesis that 1-AR blockade and mast cell stabilization independently and synergistically prevent ECM degradation by reducing LV matrix metalloprotease activation and reactive inflammatory species, resulting in improved LV remodeling and function in a clinically relevant dog model of MR.

二尖瓣反流 (MR) 通过喷射到左心房而引起低压形式的容量超负荷，从而产生独特的血流动力学应力。使用血管扩张剂进行长期治疗可降低左心室壁应力，从而延迟主动脉瓣反流的瓣膜置换术的需要；然而，目前尚无使用标准血管扩张剂或阻断 RAS 药物的慢性 MR 患者的此类数据。在临床相关的 MR 狗模型中，我们发现左室 ACE 和糜酶表达增加，左室血管紧张素 II (ANG II) 水平增加，肥大细胞数量增加，但与压力超负荷相反，不存在净纤维化。细胞外基质（ECM）降解。 1-肾上腺素能受体阻断，但不是 ACE 抑制剂或 1 型 ANG (AT1) 受体阻断，可减弱 ECM 降解并改善 LV 重塑和功能。我们的初步研究还表明，肥大细胞稳定药物可防止 ECM 降解并改善 LV 功能。此外，还有一个交感神经系统与心肌产生反应性炎症物质之间的关联。我们假设交感神经系统激活会刺激肥大细胞介导的基质金属蛋白酶激活、ECM 降解以及进行性不利的 LV 重塑和 MR 容量超负荷失败。在目标 1 中，我们将展示 1-AR 阻断相对于 AT1 受体阻断对患有中度严重程度的慢性非手术 MR 患者的疗效。我们还将检验以下假设：1-AR 阻断导致的左室重塑改善与炎症和胶原更新的血浆标志物减少有关。在目标 2 中，我们将检验以下假设：手术 MR 患者左心室心肌中基质金属蛋白酶激活和反应性炎症物质产生的程度与 3 维磁共振成像和组织标记定义的左心室重塑程度相关。在目标 3 中，我们将测试以下假设：1-AR 阻断和肥大细胞稳定通过减少 LV 基质金属蛋白酶激活和反应性炎症物质，独立并协同地防止 ECM 降解，从而改善临床相关 MR 狗模型中的 LV 重塑和功能。