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，发生在以前心脏健康的妇女分娩前不久，期间或之后。PPCM的临床过程包括心力衰竭的轻度症状，直至伴有心源性休克的暴发性过程。PPCM的病因在很大程度上是未知的和多样的。除了遗传因素，各种风险因素，如癌症，高血压疾病或应用生育治疗有助于PPCM的发展。然而，所有不同的病因导致共同的最终病理生理学途径，其中护理激素催乳素（PRL）被加工成内皮损伤性16 kDa裂解产物，其通过血管损伤导致心力衰竭。在大多数情况下，通过多巴胺D2激动剂溴隐亭和标准心力衰竭药物治疗来抑制PRL分泌的组合导致心脏功能的恢复。该治疗方案已纳入PPCM治疗的现行指南。最近对PPCM患者的诱导多能干细胞（iPSC）产生的心肌细胞进行的实验显示脂质代谢改变，这可能与PPCM病理机制有关。因此，本提案的目的是进一步阐明脂质代谢在与妊娠相关激素变化相互作用中的作用及其对PPCM中心脏功能和信号传导的影响。这些发现可能有助于发展新的战略，预防，早期诊断和更有效的治疗概念的PPCM。在该项目的第一部分，我们将使用代谢组学/脂质组学测量和心外膜脂肪组织的心脏磁共振成像分析来研究PPCM患者的脂质代谢是否失调，以及这种失调是否与妊娠期间的某些药物治疗，合并症或风险星座有关。在该项目的第二部分，我们希望澄清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，重点是对特定的作用，花生四烯酸（PG）和白三烯。除了分析PPCM患者血清中的PG和白三烯水平之外，还将在分离的成年小鼠心肌细胞和iPSC心肌细胞中分析妊娠激素和促进PPCM的16 kDa-PRL是否诱导心肌细胞PG的诱导。此外，将分析增加的PG水平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预防，诊断和治疗概念的PPCM考虑其合并症，以进一步提高可持续的心脏恢复。

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.