Metabolic dysregulation in peripartum cardiomyopathy (PPCM) – the role of lipid metabolism and arachidonic acid derivates in the pathophysiology of PPCM

围产期心肌病(PPCM)是一种心肌病，发生在先前心脏健康的妇女分娩前、分娩中或分娩后不久。PPCM的临床病程包括轻微的心力衰竭症状，直到并发PPCM的心源性休克的暴发性病程。PPCM的病因很大程度上是未知的和多样的。除了遗传因素外，各种风险因素，如癌症、高血压疾病或应用生育治疗，都有助于PPCM的发展。然而，所有不同的病因都会导致共同的最终病理生理途径，在这个过程中，哺乳激素催乳素(PRL)被加工成一种内皮损伤的16 kDa裂解产物，从而通过血管损伤导致心力衰竭。在大多数情况下，用多巴胺D2激动剂溴隐亭抑制催乳素分泌和标准的心力衰竭药物相结合会导致心功能的恢复。该治疗方案已包括在目前的PPCM治疗指南中。最近对PPCM患者的诱导多能干细胞(IPSC)所产生的心肌细胞的实验表明，脂质代谢发生了变化，这可能是PPCM的致病机制之一。因此，这项建议的目的是进一步阐明脂代谢与妊娠相关激素变化的相互作用及其对PPCM心功能和信号转导的影响。这些发现有助于制定预防、早期诊断和更有效的PPCM治疗概念的新策略。在项目的第一部分，我们将使用代谢组学/脂质组学测量和心脏磁共振成像分析心外膜脂肪组织来研究PPCM患者的脂代谢是否失调，以及这种失调是否与某些药物治疗、妊娠期间的合并症或风险星座有关。在项目的第二部分，我们想要阐明花生四烯酸代谢的改变是否在PPCM的病理生理学中发挥作用，重点是前列腺素(PG)和白三烯的具体作用。除了分析PPCM患者血清中PG和白三烯水平外，还将分析在分离的成年小鼠心肌细胞和IPSC心肌细胞中，妊娠激素和PPCM促进的16 kDa-PRL是否诱导心肌细胞PG的诱导。此外，还将分析PG水平升高对心肌细胞功能和信号转导的影响。我们的目标是建立新的PPCM的预防、诊断和治疗理念，以进一步促进可持续的心脏恢复。

Peripartum cardiomyopathy (PPCM) is a cardiomyopathy that occurs in previously heart healthy women shortly before, during or after delivery. The clinical course of PPCM includes mild symptoms of heart failure up to fulminant courses with cardiogenic shock complicating PPCM. The etiology of PPCM is largely unknown and diverse. Besides genetic factors, various risk factors such as cancer, hypertensive disorders or applied fertility treatment contribute to the development of PPCM. However, all different etiologies lead to a common final pathophysiological pathway, in which the nursing hormone prolactin (PRL) is processed into an endothelium-damaging 16kDa cleavage product, which leads to heart failure via vascular damage. In most cases, a combination of an inhibition of PRL secretion by treatment with the dopamine D2 agonist bromocriptine and standard heart failure medication leads to a recovery of cardiac function. This treatment protocol has been included in the current guidelines for the treatment of PPCM. Recent experiments with cardiomyocytes generated from induced pluripotent stem cells (iPSC) from PPCM patients show an altered lipid metabolism, which might be causally involved in the PPCM pathomechanism. Therefore, the aim of this proposal is to further elucidate the role of lipid metabolism in interaction with pregnancy-associated hormonal changes and their impact on cardiac function and signaling in PPCM. These findings could help to develop new strategies for prevention, for early diagnosis and for more efficient therapy concepts of PPCM. In part one of the project, we will use metabolomics/lipidomics measurements and cardiac magnetic resonance imaging analyzes of the epicardial adipose tissue to investigate whether the lipid metabolism is dysregulated in PPCM patients and whether this dysregulation may be associated with certain pharmacotherapies, comorbidities or risk constellations during pregnancy. In part two of the project, we want to clarify whether an altered arachidonic acid metabolism plays a role in the pathophysiology of PPCM, with focus on the specific role of prostaglandins (PG) and leukotrienes. In addition to the analysis of PG and leukotriene levels in the serum of PPCM patients, it will be analyzed in isolated adult mouse cardiomyocytes and in iPSC cardiomyocytes whether pregnancy hormones and the PPCM-promoting 16kDa-PRL induce the induction of cardiomyocyte PG. Furthermore, the effects of increased PG levels on cardiomyocyte function and signal transduction will be analyzed. We aim to establish new prevention-, diagnosis- and treatment concepts for PPCM considering their comorbidities, to further improve sustainable cardiac recovery.