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Human Semilunar Cardiac Valve Remodeling by Activated Cells From Fetus to Adult
Implications for Postnatal Adaptation, Pathology, and Tissue Engineering

Elena Aikawa, MD, PhD; Peter Whittaker, PhD; Mark Farber, MS; Karen Mendelson, MS; Robert F. Padera, MD, PhD; Masanori Aikawa, MD, PhD; Frederick J. Schoen, MD, PhD

From the Department of Pathology (E.A., M.F., K.M., R.F.P., F.J.S.) and Cardiovascular Division, Department of Medicine (M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Departments of Emergency Medicine and Anesthesiology (P.W.), University of Massachusetts Medical School, Worcester, Mass; and Center for Molecular Imaging Research (E.A.), Massachusetts General Hospital, Boston, Mass.
Correspondence to Frederick J. Schoen, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 , or Elena Aikawa, MD, PhD, Center for Molecular Imaging Research, Massachusetts General Hospital, 149 13th St, Charlestown, MA 02129 .

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 (α-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 α-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 valves possess a dynamic/adaptive structure and contain cells with an activated/immature phenotype. During postnatal life, activated cells gradually become quiescent, whereas collagen matures, which suggests a progressive, environmentally mediated adaptation.