Molecular Mechanisms of Volume Overload

由于射血进入左心房，二尖瓣反流（MR）通过诱导低压形式的容量过载而产生独特的血流动力学压力。血管扩张剂慢性治疗可减少左室壁压力，从而延迟主动脉反流瓣膜置换术的需要；然而，目前在使用标准血管扩张剂或阻断RAS的药物的慢性MR患者中尚无此类数据。在临床相关的狗MR模型中，我们发现左室ACE和酶表达增加，左室血管紧张素II （ANG II）水平增加，肥大细胞数量增加，但与压力过载相反，没有纤维化和净细胞外基质（ECM）降解。阻断1-肾上腺素能受体，但不阻断ACE抑制剂或1型ANG （AT1）受体，可减轻ECM降解，改善左室重塑和功能。我们的初步研究还表明，肥大细胞

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.