Why is the peripartum heart a substrate for dilated cardiomyopathy? A data driven investigation of molecular and cellular remodelling.

Peripartum cardiomyopathy (PPCM) is a rare form of acute heart failure with a high mortality rate that develops in women towards the end of pregnancy or early in the postpartum period. Heart transplantation is currently the only cure for end stage disease, and clinical practice is focused on the management of symptoms. The mechanisms through which the disease progresses are not well understood, and despite similar clinical characteristics to dilated cardiomyopathy (DCM) of other aetiologies it is not known how the molecular remodeling that drives the pathology differs between these two groups.

We obtained heart tissue from female patients with end stage disease receiving either heart transplantation or implantation of a left ventricular assist device, or from organ donors without a history of heart disease as a control group. Groups were matched for BMI and haemoglobin A1c status.

We utilised high resolution mass-spectrometry based bulk proteomics using TMTpro labelling. At the proteomic level, we observed regulation of canonical markers of end-stage heart failure in both PPCM and DCM hearts, consistent with similarities in the clinical phenotype. Discriminant analysis identified proteins regulated specifically in PPCM rather than in heart failure in general, and intersection with cellular gene expression profiles suggested altered mast cell activation in PPCM which was confirmed by immunohistochemistry.

In addition, we performed droplet based single nucleus RNA sequencing and spatial transcriptomics to define the repertoire of molecular and cellular modelling in PPCM, in DCM and in contrast to control human heart tissue. Integrating transcriptomic data modalities allows us to interrogate not only shifts in gene expression patterns within cell types distinct to PPCM, but also to define the importance of the local spatial context - both in terms of the cellular environment and the local gene expression. By elucidating specific molecular mechanisms we aim to enable the development of therapeutic strategies specifically for PPCM.