Preclinical Assessment of Cardiac Valve Substitutes: Current Status and Considerations for Engineered Tissue Heart Valves

Background: Heart valves regulate the unidirectional forward flow and prevent retrograde backflow of blood during the cardiac cycle. Cardiac valve disease (CVD) is observed in approximately 2.5% of the general population and the incidence increases to ~10% in elderly people. Patients with severe CVD require surgery and effective pharmacological treatments are currently not available. PROX1 is a transcription factor that regulates the development of lymphatic, venous, and lymphovenous valves (vascular valves). We identified that PROX1 is also expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 regulates cardiac valve development and disease is not known. Method and Results: We have discovered that mice lacking Prox1 in their VECs ( Prox1 ΔVEC ) develop enlarged aortic and mitral valves in which the expression of proteoglycans is increased (control, N=10; Prox1 ΔVEC , N=9, p <0.05). Echocardiography revealed moderate to severe stenosis of aortic valves of Prox1 ΔVEC mice (control, N=5; Prox1 ΔVEC , N=9, p <0.05). PROX1 regulates the expression of the transcription factor FOXC2 in the vascular valves. Similarly, we have found that the expression of FOXC2 is downregulated in the VECs of Prox1 ΔVEC mice. Specific knockdown of FOXC2 in VECs results in the thickening of aortic valves (control, N=10; shFoxc2 ΔVEC , N=8, p <0.05). Furthermore, restoration of FOXC2 expression in VECs ( Foxc2 OE-VEC ) ameliorates the thickening of the aortic valves of Prox1 ΔVEC mice ( Prox1 ΔVEC , N=9; Foxc2 OE-VEC ; Prox1 ΔVEC , N=8, p <0.05). We have also determined that the expression of platelet-derived growth factor-B ( Pdgfb ) is increased in the valve tissue of Prox1 ΔVEC mice and in PROX1 deficient sheep mitral valve VECs (MVECs) (siCtrl , N=4; siProx1 , N=4, p <0.05). Additionally, hyperactivation of PDGF-B signaling in mice results in a phenotype that is similar to Prox1 ΔVEC mice (control , N=4; Pdgfb GOF , N=3, p <0.05). Conclusion: Together these data suggest that PROX1 maintains the extracellular matrix composition of cardiac valves by regulating the expressions of FOXC2 and PDGF-B in VECs.

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New technique for construction of tissue heart valves.

Thorax ◽

10.1136/thx.35.8.611 ◽

1980 ◽

Vol 35 (8) ◽

pp. 611-614 ◽

Cited By ~ 2

Author(s):

C Manothaya ◽

S Vattanapat ◽

C Somabutr

Keyword(s):

Heart Valves ◽

New Technique ◽

Tissue Heart Valves

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Experience with tissue heart valves

The Current Status of Cardiac Surgery ◽

10.1007/978-94-011-6612-6_39 ◽

1975 ◽

pp. 260-271 ◽

Cited By ~ 2

Author(s):

Marian I. Ionescu

Keyword(s):

Heart Valves ◽

Tissue Heart Valves

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Tissue heart valves: Current challenges and future research perspectives

Journal of Biomedical Materials Research ◽

10.1002/(sici)1097-4636(19991215)47:4<439::aid-jbm1>3.0.co;2-o ◽

1999 ◽

Vol 47 (4) ◽

pp. 439-465 ◽

Cited By ~ 273

Author(s):

Frederick J. Schoen ◽

Robert J. Levy

Keyword(s):

Heart Valves ◽

Future Research ◽

Research Perspectives ◽

Tissue Heart Valves

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Possible causes for the calcification of glutaraldehyde-treated tissue heart valves and blood contacting elastomers during prolonged use in medical devices: a physico-chemical view

Biomaterials ◽

10.1016/0142-9612(81)90081-8 ◽

1981 ◽

Vol 2 (1) ◽

pp. 14-18 ◽

Cited By ~ 20

Author(s):

S.D. Bruck

Keyword(s):

Medical Devices ◽

Heart Valves ◽

Physico Chemical ◽

Tissue Heart Valves

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The work by Giulio Ceradini in explaining the mechanism of semilunar cardiac valve function

AJP Advances in Physiology Education ◽

10.1152/advan.00071.2010 ◽

2011 ◽

Vol 35 (2) ◽

pp. 110-113 ◽

Cited By ~ 3

Author(s):

Diana Troiani ◽

Ermanno Manni

Keyword(s):

Heart Valve ◽

Heart Valves ◽

Present Report ◽

Back Pressure ◽

Cardiac Valve ◽

Valve Closure ◽

Semilunar Valves ◽

Valve Function ◽

Heart Preparation ◽

Pioneer Research

Using an excised pig heart preparation with tubes, a manometer, and a visualizing apparatus, Giulio Ceradini, an Italian physiologist working in the years of 1871–1872 in Carl Ludwig's famous laboratory in Leipzig, Germany, illustrated the mechanism of closure of the semilunar valves. He was the first to conceive that the closure of the heart valves depends not on a static back pressure nor upon eddies but is primarily the consequence of the decelerated systolic efflux. This pioneer research of Ceradini was first published in German in 1872 ( 4 ). The purpose of the present report is to revisit Ceradini's pioneering experiments and his interpretation of heart valve closure, which remains as true as it was in 1872.

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Dysfunction Patterns of Epoxy-Treated Tissue Heart Valves

Kardiologiia ◽

10.18087/cardio.2019.10.n327 ◽

2019 ◽

Vol 59 (10) ◽

Author(s):

T. V. Glushkova ◽

E. A. Ovcharenko ◽

N. V. Rogulina ◽

K. Yu. Klyshnikov ◽

Yu. A. Kudryavtseva ◽

...

Keyword(s):

Heart Valves ◽

Adhesion Formation ◽

Actuarial Survival ◽

Group Iii ◽

Tissue Valve ◽

Group I ◽

Group Ii ◽

Group 2 ◽

Calcific Deposits ◽

Tissue Heart Valves

Purpose: to perform comparative morphological analysis of causes of dysfunction of epoxy-treated, xenoaortic and xenopericardial, tissues heart valves.Materials and methods. We included in this study 475 patients with mitral valve disease who have undergone heart valve replacement with tissue valve: (“KemCor”, n=211 [group 1]; “PeriCor”, n=126 [group 2]; and “UniLine”, n=138 [group 3]). Degenerative changes in 26 tissue valves (n=9 “KemCor”, n=11 “PeriCor”, and n=6 “UniLine”) explanted from the mitral position during the repeat replacement were evaluated macroscopically for the presence of calcifications, perforations, leaflet tears and ruptures, pannus, and leaflet fusion to the stent frame. Analysis of survival, freedom from dysfunction and reoperation of the studied tissue heart valves was performed for the period from January 1, 1995 to March 01, 2017.Results: Pannus overgrowth on the stent struts with extension onto the leaflets was seen on 53.8% of explanted tissue valves. “KemCor” and “PeriCor” tissue valves demonstrated over 70% rate of adhesion formation at the commissure, and in 93% of these cases there were leaflet ruptures at the commissure. Signs of calcification of different grades had 57.6% of specimens. Over 50% of “PeriCor” and “UniLine” tissue valve specimens had calcification at the stent frame. Calcified pannus was noted in 35% of all studied tissue heart valves. Interestingly, dysfunction in 53.3% of the studied tissue heart valves with detected calcification was not associated with calcific deposits. The 6-year actuarial survival for groups I, II and III was 73.5, 66.1 and 87.6%, respectively (group I vs. group II, p=0.6; group II vs. group III - p<0.05; group I vs. group III - p<0.05). The actuarial freedom from reoperation was 81.9%, 75.0% and 94.2%, respectively (pI-II>0.05; pII-III<0.05; pI-III<0.05). The actuarial freedom from dysfunction was 79.6%, 75.0%, and 94.2%, respectively (pI-II>0.05; pII-III<0.05; pI-III<0.05).Conclusion. The structure of dysfunctions of the studied tissue heart valves was represented by primary tissue failure, calcification and pannus growth. Specific design of the “UniLine” valve allowed to prevent the formation of adhesions between leaflets and the frame in the commissure buttress area, and as a result leaflet rupture from the stent struts. Xenopericardial “UniLine” tissue valves turned out to be superior to xenoaortic “KemCor” and “PeriCor” tissue valves in terms of survival, freedom from reoperations and dysfunction within the 6-year follow-up.

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