Project Details
Projekt
Metabolic dysregulation in peripartum cardiomyopathy (PPCM) – the role of lipid metabolism and arachidonic acid derivates in the pathophysiology of PPCM
Subject Area
Cardiology, Angiology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 522529821
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.
DFG Programme
Research Grants
International Connection
South Africa
Cooperation Partner
Professorin Karen Sliwa, Ph.D.
