Extracellular matrix remodeling and cell phenotypic changes in dysplastic and hemodynamically altered semilunar human cardiac valves.
BACKGROUND
Congenital cardiac valve disease is common, affecting ∼1% of the population, with substantial morbidity and mortality, but suboptimal treatment options. Characterization of the specific matrix and valve cell phenotypic abnormalities in these valves could lend insight into disease pathogenesis and potentially pave the way for novel therapies.


METHODS
Thirty-five human aortic and pulmonic valves were categorized based on gross and microscopic assessment into control valves (n=21); dysplastic valves, all except one also displaying hemodynamic changes (HEMO/DYSP, n=6); and hemodynamically altered valves (HEMO, n=8). Immunohistochemistry was performed on valve sections and flow cytometry on valvular interstitial cells.


RESULTS
While both hemodynamically altered aortic and pulmonic valves demonstrated increased collagen turnover and cell activation, prolyl 4-hydroxylase and hyaluronan increased in hemodynamically altered aortic valves but decreased in hemodynamically altered pulmonic valves relative to control valves (P<.001). HEMO/DYSP aortic valves demonstrated decreased collagen and elastic fiber synthesis and turnover compared to both hemodynamically altered aortic valves and control aortic valves (each P<.006). Valvular interstitial cells from both hemodynamically altered and HEMO/DYSP pulmonic valves showed altered cell phenotype compared to control valves (each P<.032), especially increased non-muscle myosin. Furthermore, valvular interstitial cells from hemodynamically altered pulmonic valves and HEMO/DYSP aortic and pulmonic valves each demonstrated greater size and complexity compared to control valves (each P<.05).


CONCLUSIONS
Dysplastic semilunar valves displayed alterations in collagen and elastic fiber turnover that were distinct from valves similarly exposed to altered hemodynamics as well as to control valves. These results demonstrate that dysplastic valves are not simply valves with gross changes or loss of leaflet layers, but contain complex matrix and cell phenotype changes that, with future study, could potentially be targets for novel nonsurgical treatments.
Stephens
Elizabeth H
EH
Department of Bioengineering, Rice University, Houston, TX 77251-1892, USA.
Shangkuan
Jennifer
J
Kuo
Joyce J
JJ
Carroll
Joshua L
JL
Kearney
Debra L
DL
Carberry
Kathleen E
KE
Fraser
Charles D
CD
Grande-Allen
K Jane
KJ
D000222:Adaptation, Physiological; D000293:Adolescent; D000328:Adult; D001021:Aortic Valve / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000378:metabolism; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D006330:Heart Defects, Congenital / Q000378:metabolism / Q000473:pathology*; D006349:Heart Valve Diseases / Q000378:metabolism / Q000473:pathology*; D006439:Hemodynamics; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007223:Infant; D008297:Male; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011664:Pulmonary Valve / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
D006820:Hyaluronic Acid; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase
Circulation. 1969 Jul;40(1):43-53
5792996
Lancet. 1967 Nov 4;2(7523):956-8
4167516
Circulation. 1973 Mar;47(3):575-86
4266322
J Heart Valve Dis. 2007 Mar;16(2):175-83
17484468
Tissue Eng Part A. 2010 Mar;16(3):867-78
19814589
Am J Pathol. 1979 Sep;96(3):771-80
157699
Am Heart J. 1968 Aug;76(2):173-82
5665415
Am J Physiol Heart Circ Physiol. 2009 Jun;296(6):H1898-906
19329765
Eur J Cardiothorac Surg. 2004 Dec;26(6):1098-103
15541969
Ann Thorac Surg. 2000 Nov;70(5):1594-600
11093493
Circ Res. 2006 Jun 9;98(11):1431-8
16645142
Cardiovasc Pathol. 2009 Jul-Aug;18(4):191-7
18621549
Surg Clin North Am. 1998 Oct;78(5):729-47
9891573
Pediatr Clin North Am. 1990 Feb;37(1):25-43
2408002
Pediatr Cardiol. 2001 Mar-Apr;22(2):93-101
11178660
J Heart Valve Dis. 2006 Nov;15(6):815-22
17152790
Am J Physiol Heart Circ Physiol. 2009 Mar;296(3):H756-64
19151254
Ann Biomed Eng. 2006 Nov;34(11):1655-65
17031600
J Thorac Cardiovasc Surg. 2004 Oct;128(4):552-61
15457156
J Heart Valve Dis. 2007 Nov;16(6):672-82
18095519
Tissue Eng. 2007 Sep;13(9):2281-9
17596117
Circulation. 2006 Mar 14;113(10):1344-52
16534030