Human Semilunar Cardiac Valve Remodeling by Activated Cells From Fetus to Adult

Abstract

Background-The evolution of cell phenotypes and matrix architecture in cardiac valves during fetal maturation and postnatal adaptation through senescence remains unexplored. Methods and Results-We hypothesized that valvular interstitial (VIC) and endothelial cell (VEC) phenotypes, critical for maintaining valve function, change throughout life in response to environmental stimuli. We performed quantitative histological assessment of 91 human semilunar valves obtained from fetuses at 14 to 19 and 20 to 39 weeks' gestation; neonates minutes to 30 days old; children aged 2 to 16 years; and adults. A trilaminar architecture appeared by 36 weeks of gestation but remained rudimentary compared with that of adult valves. VECs expressed an activated phenotype throughout fetal development. VIC density, proliferation, and apoptosis were significantly higher in fetal than adult valves. Pulmonary and aortic fetal VICs showed an activated myofibroblast-like phenotype (␣-actin expression), abundant embryonic myosin, and matrix metalloproteinase-collagenases, which indicates an immature/activated phenotype engaged in matrix remodeling versus a quiescent fibroblast-like phenotype in adults. At birth, the abrupt change from fetal to neonatal circulation was associated with a greater number of ␣-actin-positive VICs in neonatal aortic versus pulmonary valves. Collagen content increased from early to late fetal stages but was subsequently unchanged, whereas elastin significantly increased postnatally. Collagen fiber color analysis revealed a progressive temporal decrease in thin fibers and a corresponding increase in thick fibers. Additionally, collagen fibers were more aligned in adult than fetal valves. Conclusions-Fetal

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

“…This suggests that systemic and hemodynamic conditions within the left ventricle may affect both valves in a similar manner. Increased numbers of stromal cells, which are histologically and functionally analogous to human VICs,44, 45 contributed to thickening of valve leaflets. This is consistent with our in vitro result showing that AngII‐induced human VIC proliferation is leptin dependent.…”

Evolving Concepts of Cardiac Valve Dynamics

“…58 Second-and third-trimester fetal valves have proliferating VICs, a nascent ECM, and ␣-SMA-positive cells, indicative of myofibroblasts. Fetal VICs show an activated myofibroblast-like phenotype (␣-SMA expression), abundant embryonic myosin, and MMP collagenases, indicating an immature/activated phenotype engaged in matrix remodeling, and fetal VECs express intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, markers of an activated endothelial phenotype.…”

“…Pulmonary autograft valves in place for up to 6 years showed near-normal trilaminar and ECM architecture, viable VECs and VICs, and absence of significant pathology (Figure 7, left). 58 VICs of short-term explants (3 to 6 months) demonstrated activation with strong collagen remodeling (likely due to mechanical adaptation); in contrast, long-term explants (3 to 6 years) had quiescent fibroblast-like VICs, similar to normal valves (recall Figure 5b).…”

Biocompatibility Issue Of Tissue Engineered Heart Valves

“…A large proportion of cardiovascular conditions are due to heart valve failure [1]. The demand for heart valve replacement is estimated to grow from 290,000 a year in 2003 to more than 850,000 a year in 2050 [3]. The surgical procedure for the exchange of diseased heart valve is commonly used method of treatment in a situation in which conventional pharmacological treatments are exhausted.…”