Myocardial fibrosis in chronic aortic regurgitation: molecular and cellular responses to volume overload.
BACKGROUND
Myocardial fibrosis is common in patients with chronic aortic regurgitation (AR). Experimentally, fibrosis with disproportionate noncollagen extracellular matrix (ECM) elements precedes and contributes to heart failure in AR.


RESULTS
We assessed [3H]-glucosamine and [3H]-proline incorporation in ECM, variations in cardiac fibroblast (CF) gene expression, and synthesis of specific ECM proteins in CF cultured from rabbits with surgically induced chronic AR versus controls. To determine whether these variations are primary responses to AR, normal CF were exposed to mechanical strain that mimicked that of AR. Compared with normal CF, AR CF incorporated more glucosamine (1.8:1, P=0.001) into ECM, showed fibronectin gene upregulation (2.0:1, P=0.02), and synthesized more fibronectin (2:1 by Western blot, P<0.06; 1.5:1 by affinity chromatography, P=0.02). Proline incorporation was unchanged by AR (1.1:1, NS); collagen synthesis was unaffected (type I, 0.9:1; type III, 1.0:1, NS). Normal CF exposed to cyclical mechanical strain during culture showed parallel results: glucosamine incorporation increased with strain (2.1:1, P<0.001), proline incorporation was unaffected (1.1:1, NS), fibronectin gene expression (1.6:1, P=0.07) and fibronectin synthesis (Western analysis, 1.3:1, P<0.01; chromatography, 1.9:1, NS) were upregulated.


CONCLUSIONS
In AR, CF produce abnormal proportions of noncollagen ECM, specifically fibronectin, with relatively little change in collagen synthesis. At least in part, this is a primary response to strain imposed on CF by AR. Further study must relate these findings to the pathogenesis of heart failure in AR.
Borer
Jeffrey S
JS
Division of Cardiovascular Pathophysiology, the Howard Gilman Institute for Valvular Heart Diseases, Department of Anatomy and Cell Biology, Weill Medical College of Cornell University, New York, NY, USA. memontal@med.cornell.edu
Truter
Sharada
S
Herrold
Edmund M
EM
Falcone
Domenick J
DJ
Pena
Magda
M
Carter
John N
JN
Dumlao
Themy F
TF
Lee
Jennifer A
JA
Supino
Phyllis G
PG
D000818:Animals; D001022:Aortic Valve Insufficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D002908:Chronic Disease; D003094:Collagen / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D005355:Fibrosis; D005944:Glucosamine / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D011392:Proline / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D013314:Stress, Mechanical; D015854:Up-Regulation
D005353:Fibronectins; D012333:RNA, Messenger; D003094:Collagen; D011392:Proline; D005944:Glucosamine