Mechanisms Contributing to Pregnancy-induced Cardiac Remodeling

妊娠诱发心脏重塑的机制

• 批准号: 10587418
• 负责人: Helen E Collins
• 金额: $ 54.78万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587418
• 关键词: Accounting; Affect; Amino Acids; Biochemical; Birth; Carbon; Cardiac; Cardiac Myocytes; Cardiac health; Cardiovascular system; Catabolism; Cause of Death; Cessation of life; Contrast Echocardiography; Data; Developed Countries; Echocardiography; Energy Supply; Ensure; Enzymes; Exercise; Extracellular Matrix; Fatty Acids; Fetus; Genetic Transcription; Glucose; Glycerophospholipids; Goals; Growth; Heart; Heart failure; High Cardiac Output; Histologic; Histological Techniques; Human; Hypertrophy; Intervention; Ketone Bodies; Knowledge; Lactation; Late pregnancy; Link; Literature; Live Birth; Liver; Maternal Health Services; Maternal Mortality; Measures; Mechanics; Metabolic; Metabolism; Molecular; Mus; Myocardial; Myocardial dysfunction; Nucleotides; Nutrient; Organ; Oxidoreductase; Oxygen; Pathology; Pathway interactions; Perfusion; Physiological; Physiology; Postpartum Period; Postpartum Women; Pregnancy; Pregnancy Trimesters; Pregnant Women; Radiolabeled; Signal Transduction; Source; Structure; Testing; Tissues; Tracer; Triglycerides; Ventricular; Ventricular Remodeling; Western Blotting; Wit; angiogenesis; beta-Hydroxybutyrate; glucose metabolism; heart dimension/size; heart function; heart metabolism; hemodynamics; in vivo; indexing; ketogenesis; metabolic phenotype; osmotic minipump; overexpression; oxidation; post pregnancy; prevent; programs; stable isotope; transcriptome sequencing

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.

与其他发达国家相比，美国的孕产妇保健仍然排名较差。 美国的死亡率逐年上升，2020 年每 10 万活产儿中有 23.8 人死亡。 心血管并发症是孕妇和产后妇女死亡的主要原因；但这一比例却很低。 导致这种增长的根本因素是已知的，但由于缺乏 了解心脏如何对正常怀孕做出反应 尽管如此，众所周知，在怀孕期间，心脏会发生变化。 心脏适应母体器官和成长中的胎儿增加的代谢需求。 适应的特点是可逆的心脏生长和心室重塑，维持高心脏 然而，支持协调的分子计划。 怀孕期间和怀孕后母亲心脏的重塑仍不清楚。 新陈代谢可能对妊娠诱发的心脏重塑至关重要，正如其在其他疾病中的重要性所表明的那样 例如，增加心脏酮体（KB）代谢可以预防心脏功能障碍和 心力衰竭的重塑和葡萄糖代谢的变化调节运动引起的心脏生长。 然而，令人惊讶的是，人们对怀孕的了解却很少，因为它很重要。 可以利用它来支持母亲的心脏健康 有理由预期 KB 代谢之间存在联系。 也就是说，它们在怀孕期间提供的循环脂肪酸和甘油三酯较高； 能量输送至高度代谢的组织，并用于肝脏生酮作用。事实上，循环中的 KB 会增加。 在人类怀孕后期，被认为可以为心脏提供替代燃料来源。 我们的数据表明 KB 代谢酶 β-羟基丁酸脱氢酶 1 (Bdh1) 上调 妊娠早期心脏中的循环 KB 水平升高，而在妊娠晚期心脏中的循环 KB 水平降低 这些发现表明 KB 的可用性和母体心脏的氧化能力。 怀孕期间 KB 会增加，我们勇敢地说，怀孕期间心脏 KB 氧化可能会增加。 为合成代谢途径保留葡萄糖衍生的碳，以增加葡萄糖衍生代谢物的丰度 为了支持这一观点，我们的初步研究表明葡萄糖衍生的物质增加。 在这项研究中，我们将在怀孕期间将碳分配给核苷酸、甘油磷脂和氨基酸。 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和的程度 怀孕期间的功能；在目标 2 中，我们将评估心脏 KB 利用率对结构和功能的影响。 在目标 3 中，我们将描述 KB 代谢对母体心脏代谢重塑的影响； 了解心脏代谢如何促进妊娠引起的心脏重塑。 妊娠诱发的心脏生长将为制定干预措施以支持孕产妇提供框架 心脏健康。