Cardiomyocytes in Young Infants With Congenital Heart Disease: a Three-Month Window of Proliferation

Abstract

Perinatal reduction in cardiomyocyte cell cycle activity is well established in animal models and humans. However, cardiomyocyte cell cycle activity in infants with congenital heart disease (CHD) is unknown, and may provide important information to improve treatment. Human right atrial specimens were obtained from infants during routine surgery to repair ventricular septal defects. The specimens were divided into three groups: group A (age 1–3 months); group B (age, 4–6 months); and group C (age 7–12 months). A dramatic fall in the number of Ki67 -positive CHD cardiac myocytes occurred after three months. When cultured in vitro, young CHD myocytes (≤3 months) showed more abundant Ki67-positive cardiomyocytes and greater incorporation of EdU, indicating enhanced proliferation. YAP1 and NICD—important transcript factors in cardiomyocyte development and proliferation—decreased with age and β-catenin increased with age. Compared with those of older infants, cardiomyocytes of young CHD infants (≤3 months) have a higher proliferating capacity in vivo and in vitro. From the perspective of cardiac muscle regeneration, CHD treatment at a younger age (≤3 months) may be more optimal.

Age-Dependent Oxidative DNA Damage Does Not Correlate with Reduced Proliferation of Cardiomyocytes in Humans

“…The percentage of Ki67-positive non-cardiomyocytes in each group was 0.39 ± 0.06, 0.17 ± 0.04, and 0.11 ± 0.02, respectively ( p < 0.05; Fig 4). These results indicated that both cardiomyocyte and non-cardiomyocyte proliferation activities were decreased with age, which is consistent with previous reports [6,16]. …”

“…Although human cardiomyocytes are more tolerant to reactive oxygen species and may have greater oxidative repair capacity [25], the loss of cell cycling activity is similar to mouse cardiomyocytes [6, 16], which could be due to two possible explanations: 1) Oxidative DNA damage after birth causes permanent cell cycle arrest and subsequent recovery cannot reverse this process, and 2) Oxidative DNA damage only contributes to one component of cell cycle arrest. At birth, under increased hemodynamic stress, neonatal cardiomyocytes undergo cytoskeletal architecture reorganization in order to adjust to postnatal physical stresses.…”

“…Thus, there is a profound demand to replenish the cardiomyocytes that are lost during heart failure by either promoting the proliferation of endogenous cardiomyocytes or facilitating stem cell differentiation (3,4)[3,4]. The percentage of proliferating cardiomyocytes in mammals declines with age, especially past the neonatal period, during which both humans and rodents have more proliferating cardiomyocytes than in any other period [5, 6]. The mechanism that underlies this reduced proliferation of cardiomyocytes remains unknown.…”

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

“…In mice, this occurs during the first post-natal week 1 , coinciding with their loss of proliferative and regenerative capacity. A similar process occurs in the human heart, although with uncertain timing after birth 12,13 . Notably, a small subpopula-tion of MNDCMs persists in the adult mammalian heart.…”

Histone demethylases Kdm6ba and Kdm6bb redundantly promote cardiomyocyte proliferation during zebrafish heart ventricle maturation

“…The recognition that differentiated cardiomyocytes can re-acquire robust proliferative ability during heart regeneration in both zebrafish and mice (Jopling et al, 2010; Porrello et al, 2011; Poss et al, 2002) and that mammalian cardiomyocytes may retain some proliferative capacity during pre-adolescence (Ali et al, 2014; Haubner et al, 2016; Mollova et al, 2013; Naqvi et al, 2014; Polizzotti et al, 2015; Ye et al, 2016) has focused efforts to recapitulate these mechanisms for injury repair, notably for congestive heart failure. The role of Kdm6b histone demethylases in developmentally timed cardiomyocyte (but not cardiac progenitor) proliferation suggests the reversal of epigenetic H3K27me3 silencing marks may be an essential aspect of innate heart regeneration and a promising path to augment therapeutically delivered cardiomyocytes for heart disease.…”