The lifelong impact of fetal growth restriction on cardiac development

Abstract

Background Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. Methods A reduction in total caloric intake spanning pre-gestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. Results Cardiomyocyte proliferation and number of mononucleated cells was enhanced in the MNR-FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR-FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR-FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. Conclusions FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development.

Neonatal Morbidities of Fetal Growth Restriction: Pathophysiology and Impact

“…These studies show that the fetal heart is remodeled in a manner similar to that seen in dilated cardiomyopathy. Cardiomyocyte development is adversely affected and programmed cell death is increased in growth restricted fetal guinea pigs and sheep, with a persistence of the mononucleated, primitive cell type (70, 71). Permanent alterations in heart morphology are detected into adulthood, as evidenced by persistence in the deficits in cardiomyocyte number and cardiac hypertrophy (70).…”

Proportionality at birth and left ventricular hypertrophy in healthy adolescents

“…Similar observations have been made in precocious developers, like guinea pigs, that closely mimic human gestation. Fetal hearts isolated from growth-restricted guinea pigs are proportionately small compared to controls, but exhibit a significant reduction in cardiomyocyte number without alteration in the number of mononuclear cells [3]. However, during the final maturation phases of cardiac development, growth-restricted guinea pig hearts consistently demonstrate a high number of proliferative cardiomyocytes in the fetal and early post-natal phase relative to control hearts, but the total number of cardiomyocytes in growth restricted hearts continues to lag behind controls suggesting that cardiomyocyte expansion is impaired.…”

“…Early development and maturation of the cardiovascular system may contribute to the increased susceptibility of the heart and blood vessels to poor fetal growth. Animal models have demonstrated that cardiac mass is largely determined at birth, and the number of proliferating cardiomyocytes quickly diminishes over the first months postnatally [3,4]. This limited capacity to regenerate new cardiomyocytes forces the heart to enlarge through cardiomyocyte hypertrophy rather than hyperplasia in response to physiologic increases in systemic vascular resistance as infants grow.…”

“…This limited capacity to regenerate new cardiomyocytes forces the heart to enlarge through cardiomyocyte hypertrophy rather than hyperplasia in response to physiologic increases in systemic vascular resistance as infants grow. It was recently shown that poor fetal growth suppresses cardiomyocyte proliferation and promotes early cardiomyocyte apoptosis leading to decreased cardiomyocyte number and cardiomyocyte hypertrophy in adulthood [3]. Similarly, human cohort studies have identified an association of intrauterine growth restriction (IUGR) with cardiac remodeling in childhood [5,6].…”

“…The objective of this study was to determine associations between birth weight, birth BMI, and birth PI (birth weight/birth length 3 ) and subclinical parameters of left ventricular (LV) structure and function in a healthy adolescent population living in the southeastern U.S. We hypothesized that proportionality at birth would reveal associations between fetal growth and cardiac structure and function that are not identified by birth weight alone.…”