One of the strengths of this Program Project is our ability to make difficult and complex animal models of human disease and to follow them longitudinally with sophisticated analysis of ventricular systolic and diastolic function. These analysis have also allowed us to study the loading conditions which form the hemodynamic initiation point of hypertrophy. The constant presence of a fully-trained heart surgeon greatly facilitates the development of highly challenging models. In a Program Project Grant which seeks to define the causes and consequences of hypertrophy it is eventually necessary to measure the effects of both in the intact animal, an area where we have succeeded in a solid scientific fashion. In making physiologic measurement we have exploited the advantages of various mammalian species. The dog presents a large animal model in which physiological measurements are readily made and in which there is a wide background of the results of previous experiments. The right ventricle of the ct provides a source of pressure-hypertrophied cardiocytes and tissue wherein we have in each case a same-animal normally loaded control left ventricle. The mouse poses formidable challenges in making physiologic measurements but offers the exciting opportunity for transgenic manipulation in specifically ascribing cause and effect to genetic pathways. Dr. O'Brien adds transgenic capabilities to our previous strengths. A typical animal forms a pipeline in which the Core Facility prepares the model and studies physiology at baseline and at various time points in the progression of the overload and of the overload hypertrophy. At the termination of the in vivo studies, the myocardium of an animal which has been well characterized physiologically is now available for cell biological and molecular biological investigation. T result is that starting with the Animal Model Core there is a progression of science from intact in vivo physiologic exploration to the greater simplicity of the cell where mechanisms are more easily delineated than they are in vivo and then to the realm of molecular biology where gene-specific cause and effect relationships may be drawn. The animal models currently available are: the dog with aortic stenosis, mitral regurgitation, or myocardial infarction; the cat with right ventricular pressure overload via pulmonary artery banding or right ventricular volume overload via atrial septotomy; the mouse with left ventricular pressure overload via transverse aortic binding.
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