CELLULR REMODELING CARDIAC HYPERTROPHY

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The major goal of this research program is to investigate alterations in hemodynamics and myocardial structure associated with cardiac hypertrophy. Using the most reliable methodology available, induced alterations in myocyte size (volume, length, and cross-sectional dimensions), shape, and number are being studied in various models of cardiac hypertrophy. Modifications in capillarization and tissue content are being investigated morphometrically. Since cardiac hypertrophy may lead to congestive heart failure and greater mortality, increased knowledge of the disease process is important. Structural and hemodynamic changes will be examined in several models. Isolated myocytes will be prepared from 1, 5, and 18 month old Spontaneously Hypertensive (SHR) and Wistar Kyoto (WKY) rats. Isolated cells will also be used to study the development and reversal of aortocaval fistulas in the rat. Rats with aortocaval fistulas will be treated with thyroid hormons in an effort to produce a model of heart failure. Regional differences (right ventricular, interventicular septum, and left ventricular endomyocardium, midmyocardium and epimyocardum) in myocyte size will be correlated with changes in left and right ventricular function (eg. maximum rate of pressure rise, ventricular peak systolic and right pressure). The following myocyte changes will be measured: volume, length, cross-sectional area, and major and minor cross-sectional dimensions. Nuclear volume-cell volume relationships will be examined in mononucleated and binucleated myocytes. A 30-40% variation in mean myocyte volume and myocyte number for a given group of control animlas of similar body weight and heart weight is typically observed. Recent data suggests that this variation is genetic. Using selective breeding techniques, we hope to develop two lines of rats with significant differences in cardiac myocyte volume and number. Rats with an increased number of smaller myocytes will be compared to rats containing fewer but larger myocytes. The small and large cell lines will also be subjected to different types of cardiac overload (eg. hyperthroidism, aortocaval fistulas) to investigate the contribution of myocyte size to the pathological process of cardiac hypertrophy. Changes in mortality, left and right ventricular function, and cardiac myocyte dimensoions will be compared between rats from the two lines.