Wednesday, April 2, 2025
4/2/2025
Mechanisms Contributing to Pregnancy-induced Cardiac Remodeling - Maternal healthcare in the US continues to rank poorly in comparison to other developed countries. Maternal mortality rates in US have been increasing yearly, accounting for 23.8 deaths per 100,000 live births in 2020. Cardiovascular complications are the leading cause of death in pregnant and postpartum women; however, little is known regarding the underlying factors leading to this increase, which has been hindered by the lack of knowledge of how the heart responds to normal pregnancy. Despite this, it is known that during pregnancy, the heart adapts to meet the increased metabolic demands of maternal organs and the growing fetus. This adaptation is characterized by reversible cardiac growth and ventricular remodeling, which sustain high cardiac output during the final trimester of pregnancy. Yet, the molecular programs that support the coordinated remodeling of the maternal heart during and after pregnancy remain unknown. Coordinated changes in metabolism could be critical to pregnancy-induced cardiac remodeling, as suggested by their importance in other contexts. For example, increased cardiac ketone body (KB) metabolism prevents cardiac dysfunction and remodeling in heart failure, and changes in glucose metabolism regulate exercise-induced cardiac growth. Nevertheless, surprisingly little is known in the context of pregnancy. This knowledge is important because it could be leveraged to support maternal cardiac health. There is rationale to expect a link between KB metabolism and cardiac remodeling. To wit, circulating fatty acids and triglycerides are higher during pregnancy; they supply energy to highly metabolic tissues, and they are used for liver ketogenesis. Indeed, circulating KBs increase during late pregnancy in humans and are thought to provide alternative fuel sources for the heart. Furthermore, our data indicate that the KB metabolism enzyme, β-hydroxybutyrate dehydrogenase 1 (Bdh1), is upregulated in the heart early in pregnancy, followed in late pregnancy by higher levels of circulating KBs and reduced cardiac glucose catabolism. These findings suggest that KB availability and the capacity of the maternal heart to oxidize KBs are increased during pregnancy. We hypothesize that higher cardiac KB oxidation during pregnancy may spare glucose-derived carbon for anabolic pathways to increase the abundance of glucose-derived metabolites that facilitate cardiac growth. In support of this idea, our preliminary studies show increased glucose-derived carbon allocation to nucleotides, glycerophospholipids, and amino acids during pregnancy. In this study, we will test three aims: in Aim 1, we will determine the extent to which KB availability influences cardiac structure and function during pregnancy; in Aim 2 we will evaluate the impact of cardiac KB utilization on structural and metabolic remodeling in the maternal heart; and in Aim 3, we will delineate the influence of KB metabolism on the reversal of pregnancy-induced cardiac remodeling. Knowledge of how cardiac metabolism contributes to pregnancy-induced cardiac growth will provide a framework for developing interventions to support maternal cardiac health.
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