Transfusion Effects on Cardiomyocyte Growth and Proliferation in Fetal Sheep After Chronic Anemia

Abstract

Chronic fetal anemia results in significant cardiac remodeling. The capacity to reverse these effects is unknown. We examined the effects of transfusion on cardiomyocyte adaptations following chronic anemia in fetal sheep subjected to daily hemorrhage beginning at 109d gestation age (GA; term ∼145d). Following 10 days of anemia, one group was euthanized for comparison to age-matched controls. A separate group of anemic fetuses was transfused with red blood cells at 119d GA for comparison to controls at 129d GA. Anemia significantly increased the heart-to-body weight ratio, an effect partially ameliorated following transfusion. Cardiomyocyte dimensions were similar among all groups, suggesting an absence of hypertrophy. The percentages of mono- and binucleated cardiomyocytes were similar between groups at 119d GA, though the percentage of binucleated cells was significantly less in transfused fetuses compared to controls at 129d GA. Protein levels of mitogen activated protein kinases and protein kinase B were similar between controls and their respective intervention groups, except for a significant increase in phosphorylated c-Jun N-terminal kinase 1/2 (JNK1/2) in transfused fetuses. Thus, cardiomyocyte proliferation but not hypertrophy contributes to cardiac enlargement during fetal anemia. Transfusion results in slowing but not cessation of cardiac growth following anemia.

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

“…The goal for fetal arterial oxygen content in the anemic group was 2.0 mmol/l, as this is the arterial oxygen content measured in PI-IUGR sheep fetuses (7,28,47). The amount of blood removed daily was determined with a previously established formula taking into account fetal hematocrit and the goal arterial oxygen content (22).…”

Endocrine and other physiologic modulators of perinatal cardiomyocyte endowment

“…After a short, transient exposure, gross cardiac hypertrophy was not evident although there was a suggestion of sex-specific regulation of cellular enlargement (Lumbers et al 2009). Transient exposures complicate interpretation because the fetal heart will subsequently adjust growth to normalize heart weight, probably to match heart size to somatic circulatory demand (Jonker et al 2011). …”

Functional adaptations of the coronary microcirculation to anaemia in fetal sheep

“…; Jonker et al . ). Further, it is clear that long‐term cardiac outcomes for adults that were anaemic in utero are not normal (Broberg et al .…”

“…The changes made by the fetal heart during chronic anaemia can be explained as adaptations necessary to ensure adequate tissue oxygenation and enable survival to birth (Davis & Hohimer, 1991). This stress-induced process disrupts normal myocardial growth and maturation, and transfusion to restore fetal haematocrit does not completely return these trajectories to normal (Carter et al 1990;Jonker et al 2011). Further, it is clear that long-term cardiac outcomes for adults that were anaemic in utero are not normal (Broberg et al 2003;Yang et al 2008;Wallace et al 2011).…”