Even though the amount of collagen within the myocardium is quite small, its high stiffness dictates that it contributes to the viscoelastic behavior of the myocardium. Collagen, therefore, determines the extent to which myocytes generate force and, consequently, the O2 they consume. The collagen concentration of the hypertrophied, pressure-overloaded human myocardium is increased and, in some cases, its growth appears to exceed that of cardiac muscle. Collagen may, therefore, be responsible for the failure of the previously compensated heart. Our specific objectives are to examine the collagen composition and the rate of collagen biosynthesis of the experimentally pressure-overloaded myocardium, as well as its cultured fibroblasts and to determine its impact on the passive and active mechanical properties and O2 utilization of the hypertrophied myocardium. Three experimental models of left ventricular pressure-overload will be examined during their evolutionary, compensated and decompensated stages. These include spontaneous hypertension (rat) renovascular hypertension (rat and macaque), and constriction of the ascending aorta (rat). Cardiac function is monitored serially and at each stage of hypertrophy by direct recording of left ventricular pressure and progressive exercise testing to determine maximum O2 uptake and anaerobic threshold. At pre-determined intervals each population is sacrificed and divided equally for collagen composition and function studies respectively. Comparisons are drawn to age/sex-matched, sham operated controls. For the collagen studies, extirpated hearts are weighed and an equatorial cross-section is removed for staining and morphometric determination of collagen volume fraction and distribution. The remainder of the heart is either frozen for analysis of hydroxyproline concentration and collagen types, or labelled with C14 proline and then frozen for biosynthesis studies. In the function studies, hearts are removed, perfused and instrumented to monitor ventricular pressure, volume and flow. Their aerobic capacity to increments in myocardial work is determined, followed by an examination of their diastolic and systolic elastance and resistance. Thereafter, a dilute purified collagenase solution, free of proteases, is infused to determine the functional role of collagen. Finally, pathologic hypertrophy is compared to physiologic hypertrophy of exercise training and an experimental model of myocardial fibrosis (allylamine), and the effectiveness of various therapies (reserpine, d-penicillamine and captopril), on preventing abnormal collagen growth in pathologic hypertrophy will be assessed.
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