Induced Pluripotent Stem Cell-derived Cardiomyocytes Uncover High Levels of the Transcriptional Factor STAT3 in Peripartum Cardiomyopathy

Background and Aim: Peripartum cardiomyopathy (PPCM) is a rare but serious condition of unknown cause. The transcription factor STAT3 regulates a protective and reparative response in the heart. Downregulation of STAT3 in cardiomyocytes and subsequent oxidative stress have been implicated in the pathogenesis of PPCM. Thus, we aimed to model PPCM in induced pluripotent stem cell (IPSC)-derived cardiomyocytes and determine whether low levels of STAT3 characterize PPCM IPSC-derived cardiomyocytes.

Methods and Results: To model and study the pathogenesis of PPCM we created patient-specific cardiomyocytes from IPSC which were obtained from PPCM and healthy donors. First, we generated the IPSC cells from dermal tissue biopsies and differentiated them toward beating cardiomyocytes. Next, to determine the effect of adrenergic stimulation on STAT3 in PPCM cardiomyocytes independent of pregnancy and pregnancy hormones, we exposed the IPSC-derived cardiomyocytes to isoprenaline (Iso) and extracted protein. We measured the levels of STAT3 by Western blot analysis. Contrary to the shared theory, we found that the basal levels of both STAT3 isoforms (α and β) were higher in PPCM cardiomyocytes (Figure). Furthermore, the amount of STAT3α and β did not vary after Iso stimulation and remained elevated to a larger extent in PPCM cardiomyocytes than in control cardiomyocytes (Figure). Of interest, the proportions between STAT3α and β were constant in the PPCM cardiomyocytes even after Iso stimulation, while high doses of Iso increased the proportions between STAT3α and β in the healthy cardiomyocytes.

Conclusions: We show, for the first time, that IPSC-derived cardiomyocytes can be used to model PPCM. In contrast to our hypothesis, IPSC-derived cardiomyocytes from PPCM patients are characterized by higher levels of STAT3 and lower levels of VEGF compared with normal controls. Our data challenge the theory that reduced levels of the transcriptional factor STAT3 are responsible for the development of PPCM.