Pregestational diabetes alters cardiac structure and function of neonatal rats through developmental plasticity

Abstract

Pregestational diabetes (PGDM) leads to developmental impairment, especially cardiac dysfunction, in their offspring. The hyperglycemic microenvironment inside the uterus alters the cardiac plasticity characterized by electrical and structural remodeling of the heart. The altered expression of several transcription factors due to hyperglycemia during fetal development might be responsible for molecular defects and phenotypic changes in the heart. The molecular mechanism of the developmental defects in the heart due to PGDM remains unclear. To understand the molecular defects in the 2-days old neonatal rats, streptozotocin-induced diabetic female rats were bred with healthy male rats. We collected 2-day-old hearts from the neonates and identified the molecular basis for phenotypic changes. Neonates from diabetic mothers showed altered electrocardiography and echocardiography parameters. Transcriptomic profiling of the RNA-seq data revealed that several altered genes were associated with heart development, myocardial fibrosis, cardiac conduction, and cell proliferation. Histopathology data showed the presence of focal cardiac fibrosis and increased cell proliferation in neonates from diabetic mothers. Thus, our results provide a comprehensive map of the cellular events and molecular pathways perturbed in the neonatal heart during PGDM. All of the molecular and structural changes lead to developmental plasticity in neonatal rat hearts and develop cardiac anomalies in their early life.

Evaluation of fetal myocardial performance index in gestational diabetes mellitus

“…Transmission of the electrical impulse for coordinated contractions occurs via the cardiac conduction system of the heart. In the study by Alam et al in newborn rats born from diabetic rats, a decrease in the expression of Bmp4 and Pitx2 , two genes associated with the regulation of the cardiac conduction system, was observed 32 . These data may be relevant to our findings of the PR interval showing altered cardiac electrophysiology in neonates born to pregnancies with gestational diabetes.…”

“…In the study by Alam et al in newborn rats born from diabetic rats, a decrease in the expression of Bmp4 and Pitx2, two genes associated with the regulation of the cardiac conduction system, was observed. 32 These data may be relevant to our findings of the PR interval showing altered cardiac electrophysiology in neonates born to pregnancies with gestational diabetes. Regarding the fetal cardiac effects of hyperglycemia, Turan et al reported decreased fetal myocardial function in the first trimester of diabetic pregnancies.…”

ER stress and lipid imbalance drive diabetic embryonic cardiomyopathy in an organoid model of human heart development

“…In line with this, time course qPCR analysis revealed disparities in the regulation of GATA4 , NKX2-5 , and TBX5 at different time points throughout development, highlighting the importance of fine transcription control during early development. PGDHOs also presented arrhythmias and reduction in beat frequency, a phenotype that has not been described in diabetic embryonic cardiomyopathy but has been observed in neonatal rats from diabetic mothers ( Alam et al., 2022 ).…”

ER stress and lipid imbalance drive embryonic cardiomyopathy in a human heart organoid model of pregestational diabetes

“…These phenotypes were consistent with outcomes found in PGD-induced CHD in animal models and human clinical reports 15,55,56,60 . PGDHOs also presented arrythmias and reduction in beat frequency as determined by calcium imaging, a phenotype that has not been described in diabetic embryonic cardiomyopathy but has been observed in neonatal rats from diabetic mothers 61 and diabetic human adults, which typically exhibit reduced calcium pump activity leading to diastolic dysfunction 62 .…”