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，美国的孕产妇医疗保健的排名较差。 美国的死亡率每年都在增加，占2020年每10万活产死亡的23.8例死亡。 心血管并发症是孕妇和产后妇女死亡的主要原因。但是，很少 关于导致这一增加的基本因素已知，由于缺乏 了解心脏如何应对正常妊娠。尽管如此，众所周知，在怀孕期间 心脏适应以满足孕产妇器官和胎儿不断增长的代谢需求。这 适应的特征是可逆心脏增长和心室重塑，可维持高心脏 在怀孕的最后三个月的产量。但是，支持协调的分子程序 怀孕期间和妊娠后母亲心脏的重塑仍然未知。协调的变化 代谢对于怀孕引起的心脏重塑至关重要，如它们在其他方面的重要性所表明的 上下文。例如，心脏酮体（KB）代谢增加可防止心脏功能障碍和 心力衰竭的重塑以及葡萄糖代谢的变化调节运动引起的心脏生长。 然而，在怀孕的背景下，鲜为人知的知之甚少。这些知识很重要，因为它 可以利用以支持孕产妇心脏健康。有理由可以期望KB代谢之间有联系 和心脏重塑。为了机智，怀孕期间循环脂肪酸和甘油三酸酯较高。他们提供 能量对高度代谢组织，它们用于肝脏生酮。确实，循环KBS增加 在人类怀孕晚期期间，被认为为心脏提供替代的燃料来源。此外， 我们的数据表明，KB代谢酶，β-羟基丁酸脱氢酶1（BDH1）已更新 在怀孕初期的心脏中，随后怀孕后期，循环KB的水平较高，心脏降低 葡萄糖分解代谢。这些发现表明，KB的可用性和母体心脏对氧化物的能力 怀孕期间KBS增加。我们假设怀孕期间较高的心脏KB氧化可能 备用葡萄糖衍生的碳，用于合成代谢途径，以增加葡萄糖衍生代谢物的抽象 这促进了心脏增长。为了支持这一想法，我们的初步研究表明葡萄糖衍生增加 怀孕期间，碳分配给核苷酸，甘油磷脂和氨基酸。在这项研究中，我们将 测试三个目标：在AIM 1中，我们将确定KB的可用性影响心脏结构和 怀孕期间的功能；在AIM 2中，我们将评估心脏KB利用对结构和结构的影响 在母性心脏中进行代谢重塑；在AIM 3中，我们将描述KB代谢对 妊娠引起的心脏重塑的逆转。了解心脏代谢如何促进 怀孕引起的心脏增长将为开发干预措施提供支持母体的框架 心脏健康。