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.
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