Abstract Body: Background:
Peripartum cardiomyopathy (PPCM) is a life-threatening pregnancy-associated cardiomyopathy. PPCM overlaps phenotypically and genetically with dilated cardiomyopathy (DCM), including enrichment of TTN truncating variants (TTNtv). A two-hit model has been proposed in which genetic predisposition and pathological pregnancy stress – including preeclampsia – converge to precipitate disease. However, whether preeclamptic plasma selectively impairs TTNtv cardiomyocytes remains unknown.
Methods:
We exposed control and heterozygous TTNtv human iPSC-cardiomyocytes (iPSC-CM) for 48 hours to 2% plasma from healthy pregnant women or women with preeclampsia collected near term (~39 weeks), alongside untreated conditions. Contractile force, oxygen consumption rate (OCR), cell painting, and transcriptomics were assessed.
Results:
Contractile force was unchanged in control iPSC-CM across untreated, healthy, and preeclamptic plasma conditions. In TTNtv iPSC-CMs, healthy plasma caused a non-significant reduction in contractile force versus untreated cells (p=0.1), whereas preeclamptic plasma induced a significant 36% reduction in force versus healthy plasma, worsening the DCM-like phenotype. Etomoxir-sensitive OCR was reduced after preeclamptic versus healthy plasma in both genotypes, with a greater reduction in TTNtv cells, indicating impaired fatty acid oxidation. Cell painting showed reduced mitochondrial intensity in TTNtv under preeclamptic condition. Transcriptomic showed that healthy and preeclamptic plasma change gene expression relative to untreated in both lines, but WT and TTNtv engage distinct programs. In the healthy-versus-preeclamptic comparison, WT cells had no differentially expressed genes at FDR<0.05, whereas TTNtv cells showed 27 genes involving mitochondrial/oxidative phosphorylation programs.
Conclusions:
Pathological pregnancy plasma had limited functional effects in control cardiomyocytes but exacerbated contractile and metabolic vulnerability in TTNtv cardiomyocytes, supporting a two-hit model of PPCM. This human model separates physiologic pregnancy adaptation from pathological pregnancy stress and provides a platform to investigate mechanisms and test therapies relevant to PPCM.