Cardiac muscle is tethered within a fibrillar collagen matrix that serves to maximize force generation. Left ventricular pressure overload (LVPO) and hypertrophy (LVH) lead to excess collagen accumulation, or fibrosis (FIB). We observed FIB without cell necrosis (reactive FIB) during the evolutionary and early established phases of LVH while scar formation (reparative FIB) was present weeks later. These were structurally distinct patterns of fibrosis. In both forms of FIB, a structural and biochemical remodeling of collagen occurred with either beneficial or detrimental modifications of the systolic stress- stain relation of the intact myocardium, respectively. Accordingly, it continues to be our hypothesis that LVPO leads to reactive and reparative FIB which accounts for an alteration in the mechanical behavior of the hypertrophied myocardium.
Our first aim i s to determine the role of collagen concentration and content, and Its fibrillar types, distribution and structure in altering the systolic stress-strain relation In LVH. These issues will be addressed by a) raising the collagen/muscle mass ratio secondary to either increments or decrements in the respective volumes of collagen or muscle compartments; h) comparing subendocardial to patchy transmural FIB; and c) using the tight skin mouse with its excess type 1 collagen. Picrosirius red and polarization microscopy will be used to identify the different patterns of FIB and the structural nature and composition of fibrous tissue formation. Why collagen remodeling occurs with LVPO leads us to focus on myocardial fibroblasts- (Fb). In response to B adrenergic stimulation and in the absence of cell necrosis, we observed Fb proliferation in regions where wall stress is greatest.
Our second aim i s to determine whether wall stress-mediated myocardial norepinephrine (NE) release is the signal and Fb receptors the transducer of Fb proliferation and collagen synthesis in LVPO, We will monitor these events cAMP formation when a) total myocardial NE prior to LVPO is reduced pharmacologically or regionally by chemical denervation, and the influence of circulating NE is eliminated, b) wall stress is controlled in the denervated heterotopically transplanted heart, and c) pharmacologic probes of a and B receptors are used in adult cardiac fibroblast culture to assess their role in mediating these events in normal and hypertrophied hearts.
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