Mechanisms Contributing to Pregnancy-induced Cardiac Remodeling

与其他发达国家相比，美国的孕产妇保健仍然排名靠后。产妇 美国的死亡率逐年上升，2020年每10万例活产死亡23.8例。 心血管并发症是孕妇和产后妇女死亡的主要原因;然而， 关于导致这一增长的根本因素， 了解心脏对正常妊娠的反应。尽管如此，据了解，在怀孕期间， 心脏适应以满足母体器官和生长中的胎儿增加的代谢需求。这 适应的特征是可逆的心脏生长和心室重塑，这维持了高的心脏功能。 在怀孕的最后三个月的输出。然而，支持协调的分子程序 妊娠期间和妊娠后母体心脏的重塑仍然未知。协调变化， 代谢可能是至关重要的妊娠诱导的心脏重塑，因为他们的重要性，在其他建议， contexts.例如，增加的心脏酮体（KB）代谢防止心脏功能障碍， 心力衰竭中的重塑和葡萄糖代谢的变化调节运动诱导的心脏生长。 然而，令人惊讶的是，在怀孕的背景下知之甚少。这些知识很重要，因为它 可以用来支持产妇的心脏健康。有理由预期KB代谢之间的联系 和心脏重塑也就是说，循环脂肪酸和甘油三酯在怀孕期间更高，它们提供 高代谢组织的能量，并用于肝酮生成。事实上，流通的知识银行增加了 在人类怀孕后期，被认为是心脏的替代燃料来源。此外，委员会认为， 我们的数据表明，KB代谢酶β-羟基丁酸脱氢酶1（Bdh 1） 在妊娠早期心脏中，随后在妊娠晚期，循环KBs水平较高， 葡萄糖催化剂这些结果表明，KB的可用性和母体心脏的氧化能力， KBs在怀孕期间增加。我们推测，妊娠期间心脏KB氧化水平升高可能 为合成代谢途径保留葡萄糖衍生碳，以增加葡萄糖衍生代谢物的丰度 促进心脏生长。为了支持这一观点，我们的初步研究表明， 碳分配到核苷酸，甘油磷脂和氨基酸在怀孕期间。在这项研究中，我们将 测试三个目标：在目标1中，我们将确定KB可用性影响心脏结构的程度， 在目的2中，我们将评估心脏KB利用对结构和功能的影响， 在目标3中，我们将描述KB代谢对母体心脏的影响。 逆转妊娠引起的心脏重塑了解心脏代谢如何有助于 妊娠诱导的心脏生长将为制定干预措施提供框架， 心脏健康

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.