Role of genetic and epigenetic alterations in central signaling modules in the pathophysiology of peripartum cardiomyopathy

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Over the past decade, knowledge on the pathophysiological mechanisms behind peripartum cardiomyopathy (PPCM) has steadily grown. PPCM is defined as onset of left ventricular (LV) systolic dysfunction in the last month of pregnancy and the months following delivery in previously healthy women. We estimate that around 1 in 1500-2000 pregnancies are affected in Germany; ‘hot spots’ in Africa report a prevalence of 1 in 100 pregnancies. Although increased awareness and recent progress in the treatment and management of PPCM has improved outcomes, patients remain at high risk for sudden death, relapse during subsequent pregnancies and dependence on long-term heart failure medication. We discovered that unbalanced oxidative stress leads to the production of an angiostatic fragment of the nursing hormone prolactin (PRL), the 16-kDa PRL, which appears to induce and drive PPCM. Preliminary data suggest that 16-kDA PRL signals via the plasminogen activator inhibitor-1 (PAI-1)/uPAR system in PPCM and that PAI-1 is up-regulated in blood samples and in iPSC-derived cardiomyocytes from PPCM patients. PAI-1 remains elevated in PPCM patients after recovery of LV function, suggesting that it may be a predisposing factor for PPCM. Beside PAI-1, several additional serum factors had not normalized at follow-up in PPCM patients with recovered LV function, indicating ongoing pathomechanisms despite functional recovery. Circulating microRNAs (miRNA) seem to contribute to the PPCM pathophysiology and a miRNA array showed differential expression of numerous miRNAs between PPCM patients and healthy postpartum controls. Finally, potential targets for these differentially regulated circulating miRNAs are STAT3, PAI-1 and the Notch1 signalling pathway. Based on these data, we will address the following objectives: 1) Investigate regulatory mechanisms for PAI-1 in PPCM and analyse if PAI-1 up-regulation is essential for PPCM development. In addition, analyse whether PAI-1 is suited as a diagnostic tool and therapeutic target in PPCM. 2) Determine the time course of circulating cytokines, hormones and growth factors involved in inflammation, metabolism and cancer, analyse regulatory mechanisms for deregulation of these factors in PPCM, and analyse their potential role in acute and long-term pathologies of PPCM. 3) Analyse the potential role of circulating miRNAs for acute and long-term pathologies of PPCM and their potential relation to the serum factor profile to gain novel insights into acute and on-going pathologies and (epigenetic) modulators in PPCM disease. 4) Investigate the regulation (by miRNAs) and role of cardiac Notch1 signalling for protection and healing in PPCM. The present project aims to improve the understanding of underlying pathomechanisms in PPCM, provide novel measures to predict long-term outcome and develop novel treatment options for PPCM patients towards better and more stable recovery to limit long-term morbidity and mortality.