The gain and loss of function strategies employed in the SCOR projects using transgenic over-expression and gene-targeted ablation of candidate genes have provide important insights into the cellular mechanisms that underlie hypertrophy and heart failure. Whereas contractility is assessed using a hierarchical approach that examines the mechanics of constituent myocytes, isolated myofibers, and the isolated heart, an essential component of this SCoR is the critical examination of cardiovascular physiology in the intact animal under various physiologic and pathologic conditions. In this regard, the heart is characterized as a muscular pump coupled to the systemic and venous circulations; analysis of integrated cardiovascular performance incorporates the compensatory molecular, geometric vascular and neurohumoral mechanisms that act to produce the ultimate phenotypic consequences of a specific genetic modification. Accordingly, the goals of the Mouse Physiology Core are: 1) To perform serial, non-invasive modification. Accordingly, the goals of the Mouse Physiology Core are: 1) To perform serial, non-invasive """"""""screening"""""""" (i.e. an initial characterization) of cardiovascular phenotypes with echocardiography in order to detect mutational and pathological changes in genetically and physiologically altered mice; 2) To fully characterize cardiovascular phenotype changes, including LV remodeling, LV mass, and systolic and diastolic functions, using non-invasive (echocardiography) and invasive (catheterization) methods; 3) To localize abnormal intracellular calcium handling and assess excitation-contraction coupling in vivo using parameters of force-interval behavior (force- frequency relation, mechanical and relaxation restitution, post- extrasystolic potentiation, and the response to ryanodine) in genetically and physiologically altered animals; and 4) To create acute (volume loading, pharmacological challenges) and chronic pathophysiological perturbations (transverse aortic banding, aortocaval fistula) that can be superimposed on genetically altered animals. Using these methods, the interplay among the intrinsic properties of cardiomyocytes, fiber mechanics, extracellular matrix, chamber properties, loading conditions, and their modulation by neurohormonal compensatory mechanisms, can be assessed to understand the functional role of a specific protein, its abundance, and its isoform in the in vivo context.
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