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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.

二尖瓣返流（MR）由于射血进入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。血管扩张剂长期治疗可降低LV壁应力，从而延迟主动脉瓣返流患者的瓣膜置换术需求;然而，目前在使用标准血管扩张剂或RAS阻断剂的慢性二尖瓣返流患者中尚无此类数据。在临床相关的MR犬模型中，我们发现LV ACE和糜酶表达增加，LV血管紧张素II（ANG II）水平升高，肥大细胞数量增加，但与压力超负荷相反，没有纤维化伴净细胞外基质（ECM）降解。1-肾上腺素能受体阻断剂，而不是ACE抑制剂或1型ANG（AT 1）受体阻断剂，减弱ECM降解和改善LV重塑和功能。我们的初步研究还表明肥大细胞稳定药物防止ECM降解并改善LV功能。此外，还有一个交感神经系统和反应性炎症物质的心肌产生之间的关联。我们假设交感神经系统激活刺激肥大细胞介导的基质金属蛋白酶激活、ECM降解和进行性不良LV重构以及MR容量超负荷失败。在目的1中，我们将显示1-AR阻断剂对中度慢性非手术MR患者的疗效超过AT 1受体阻断剂。我们还将检验1-AR阻断导致的LV重构改善与炎症和胶原蛋白周转的血浆标志物减少有关的假设。在目标2中，我们将检验以下假设：手术MR患者的LV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三维磁共振成像和组织标记定义的LV重构程度相关。在目标3中，我们将检验1-AR阻断和肥大细胞稳定化通过减少LV基质金属蛋白酶活化和反应性炎症物质，独立和协同地防止ECM降解，从而在临床相关MR犬模型中改善LV重塑和功能的假设。