CORE-- MODEL

Medical University Of South Carolina, Charleston SC

Investigators

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Abstract

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 analyses have also allowed us to study the effects of changes in loading conditions or the effects of injury on cardiac hypertrophy and remodeling which form the hemodynamic initiation point of these processes. In a Program Project, which seeks to define the causes and consequences of hypertrophy and remodeling, it is eventually necessary to measure the effects of both the causes and consequences in vivo in the intact animal, in vitro in isolated cardiac tissue and in vitro in isolated cardiocytes. These are areas where we have succeeded in a solid scientific fashion. In making clinically relevant models and physiologic measurements, we have exploited the advantages of various mammalian species. The pig presents a large animal model in which physiological measurements can readily be made, cardiac physiology and coronary anatomy is comparable to man, and in which there is a wide background of the results of previous experiments. The right ventricle of the cat offers study of papillary muscles for examination of classic muscle mechanics and the effect of pathologic states on those mechanics. Importantly for this work, it also provides a source of pressure or volume - hypertrophied right ventricular cardiocytes and tissue wherein we have in each case, a same-animal normally loaded control left ventricle. While the mouse poses formidable challenges in making relevant models and physiologic measurements, it offers the exciting opportunity for transgenic manipulation in specifically ascribing cause and effect to various genetic pathways. We have successfully developed the ability to make clinically relevant models, physiologic measurements, and gene transfer constructs involving transgenic mouse lines, adenoviral cardiocyte transfections and viral infections of intact left ventricle in mice. In addition, we have successfully developed the ability to make in vivo and in vitro physiologic measurements, from which changes in volume, mass, geometry, systolic and diastolic function can be assessed. A typical animal model forms a pipeline in which the Core Facility prepares the model and studies physiology at baseline and at various time points during the progression of the overload or injury to hypertrophy and remodeling. At the termination of the in vivo studies, the myocardium of an animal, which has been well characterized physiologically, is now available for muscle physiology, cell biological and molecular biological investigation. The 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 pig with 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 banding, and mouse with myocardial infarction.