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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031701-03
Application #
3342913
Study Section
(SRC)
Project Start
1983-09-30
Project End
1988-09-29
Budget Start
1985-09-30
Budget End
1986-09-29
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Michael Reese Hosp & Medical Center (Chicago)
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60616
Katwa, L C; Sun, Y; Campbell, S E et al. (1998) Pouch tissue and angiotensin peptide generation. J Mol Cell Cardiol 30:1401-13
De Carvalho Frimm, C; Sun, Y; Weber, K T (1997) Angiotensin II receptor blockade and myocardial fibrosis of the infarcted rat heart. J Lab Clin Med 129:439-46
Katwa, L C; Campbell, S E; Tyagi, S C et al. (1997) Cultured myofibroblasts generate angiotensin peptides de novo. J Mol Cell Cardiol 29:1375-86
Sun, Y; Ramires, F J; Weber, K T (1997) Fibrosis of atria and great vessels in response to angiotensin II or aldosterone infusion. Cardiovasc Res 35:138-47
Sigusch, H H; Campbell, S E; Weber, K T (1996) Angiotensin II-induced myocardial fibrosis in rats: role of nitric oxide, prostaglandins and bradykinin. Cardiovasc Res 31:546-54
Kovacs, A; Kandala, J C; Weber, K T et al. (1996) Triple helix-forming oligonucleotide corresponding to the polypyrimidine sequence in the rat alpha 1(I) collagen promoter specifically inhibits factor binding and transcription. J Biol Chem 271:1805-12
Ou, R; Sun, Y; Ganjam, V K et al. (1996) In situ production of angiotensin II by fibrosed rat pericardium. J Mol Cell Cardiol 28:1319-27
Sun, Y; Weber, K T (1996) Angiotensin-converting enzyme and wound healing in diverse tissues of the rat. J Lab Clin Med 127:94-101
Frimm, C de C; Sun, Y; Weber, K T (1996) Wound healing following myocardial infarction in the rat: role for bradykinin and prostaglandins. J Mol Cell Cardiol 28:1279-85
Slight, S H; Ganjam, V K; Gomez-Sanchez, C E et al. (1996) High affinity NAD(+)-dependent 11 beta-hydroxysteroid dehydrogenase in the human heart. J Mol Cell Cardiol 28:781-7

Showing the most recent 10 out of 91 publications