Cardiomyocyte proliferation and regeneration in congenital heart disease

Abstract

Despite advances in prenatal screening and a notable decrease in mortality rates, congenital heart disease (CHD) remains the most prevalent congenital disorder in newborns globally. Current therapeutic surgical approaches face challenges due to the significant rise in complications and disabilities. Emerging cardiac regenerative therapies offer promising adjuncts for CHD treatment. One novel avenue involves investigating methods to stimulate cardiomyocyte proliferation. However, the mechanism of altered cardiomyocyte proliferation in CHD is not fully understood, and there are few feasible approaches to stimulate cardiomyocyte cell cycling for optimal healing in CHD patients. In this review, we explore recent progress in understanding genetic and epigenetic mechanisms underlying defective cardiomyocyte proliferation in CHD from development through birth. Targeting cell cycle pathways shows promise for enhancing cardiomyocyte cytokinesis, division, and regeneration to repair heart defects. Advancements in human disease modeling techniques, CRISPR-based genome and epigenome editing, and next-generation sequencing technologies will expedite the exploration of abnormal machinery governing cardiomyocyte differentiation, proliferation, and maturation across diverse genetic backgrounds of CHD. Ongoing studies on screening drugs that regulate cell cycling are poised to translate this nascent technology of enhancing cardiomyocyte proliferation into a new therapeutic paradigm for CHD surgical interventions.

Keywords: cardiomyocytes; congenital heart disease; proliferation; regenerative medicine.

FIGURE 1

Schematic diagram of CHD malformations and underlying mechanisms. (A): In comparison to a normal heart, the abnormal structures in CHD cases are evident in the connections between the left and right chambers or vessels, morphological abnormalities, and structural defects. (B): CHD is associated with multilayered mechanisms, including chromosomal aberrations, altered epigenetic mechanisms, genetic variations or mutations, transcriptomic changes, noncoding RNA modulations, disturbed transcription factor interactions, and environmental factors. CHD, congenital heart disease.

FIGURE 2

Genetic or epigenetic alterations related to CHD during heart development. Genetic and epigenetic alterations underlying CHD can be identified using next‐generation sequencing techniques. Functional validation through loss‐of‐function studies or genetic manipulation models can classify the involved genes into (1) pathogenic genes (These typically encode cardiogenic transcription factors that directly regulate cardiomyocyte cell cycle activity in CHD through well‐established mechanisms), (2) susceptibility genes (such as pathway receptors or kinases, indirectly influence cardiac cell cycling and contribute to an increased risk of CHD), and (3) secondary genes (such as growth factors or microRNAs, have broader effects on cell cycling and may not be specific to the heart but can influence overall cell proliferation). CHD, congenital heart disease.

FIGURE 3

Defective cardiomyocyte proliferation and maturation in CHD after birth. In contrast to healthy subjects, CHD infants exhibit a reduced number of mononuclear, diploid cardiomyocytes, but increased cell populations with multinucleation and polyploidization due to impaired cell cycle regulation during development. After birth, these abnormal cardiomyocytes in CHD patients respond poorly to cues that trigger healthy heart growth and maturation (developmental hormones or increased workload). In contrast, healthy cardiomyocytes undergo a controlled enlargement (hypertrophic growth) and improve their function as the body grows. CHD, congenital heart disease.