Letter by Hilfiker-Kleiner et al Regarding Article, “Modeling Peripartum Cardiomyopathy With Human Induced Pluripotent Stem Cells Reveals Distinctive Abnormal Function of Cardiomyocytes”
Authors: Denise Hilfiker-Kleiner, Karen Sliwa, Johann Bauersachs
Journal: Circulation (2019)

We read with interest the article by Naftali-Shani et al, 1 which provides an interesting disease-modeling concept.However, we would like to ask the authors how they relate their model of human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) stimulation with isoprenaline to the peripartum (patho-)physiology which includes mechanical stress, alterations in hemodynamics, and multiple additional factors, including changes in many hormones beyond increased β-adrenergic agonists.It also is not clear for us why the present study 1 can address the role of signal transducer and activator of transcription 3 (STAT3) in peripartum cardiomyopathy (PPCM) by only looking at STAT3 expression in iPSC-CMs.Published literature suggests no evidence that the transcription of STAT3 is reduced in patients with PPCM 2,3 because this would probably lead to embryonic and fetal death because STAT3 is essential for development.In turn, it has been shown that the systemic effects associated with peripartum stress, such as hyperosmolar conditions attributable to extensive bleeding and fluid loss, lead to a posttranslational degradation of STAT3, explaining the low STAT3 protein levels reported in cardiac biopsies from patients with PPCM. 2,3In our opinion, this aspect of STAT3 regulation cannot be addressed by the model used in the present study.Deregulated STAT3 is only 1 factor that may promote PPCM.Other factors associated with PPCM pathomechanisms, such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha, have been described. 4In fact, the expression pattern of vascular endothelial growth factor and soluble fms-like tyrosine kinase 1 observed in iPSC-CMs from the patients with PPCM in the present study 1 is highly similar to the mouse model for PPCM with a cardiomyocyte-specific deletion of peroxisome proliferator-activated receptor gamma coactivator 1-alpha. 4Could the authors explain why they did not address this aspect in their study?Along the same line, multiple pathomechanisms (including STAT3 degradation) seem to induce PPCM, but increased oxidative stress is viewed as a downstream pathway common to most PPCM conditions.Therefore, it would be interesting to know whether the authors did measure oxidative stress in their model.Because oxidative stress (and not STAT3) is the trigger for prolactin cleavage and the base for the prolactin hypothesis, could the authors comment on this aspect especially because they challenge the prolactin hypothesis?The authors report that 1 patient who had PPCM with a clear family history for cardiomyopathies carried a truncating mutation in Titin likely to cause a genetic cardiomyopathy.Did the authors check for additional mutations present in the other patients?About 15% of patients with PPCM carry mutations in sarcomeric genes 5 ; however, besides these mutations, evidence is lacking so far for a genetic cause for PPCM in most patients.In the absence of any genetic evidence, it would be great if the authors could explain their expectation that iPSC-CMs from patients with PPCM differ from