An Unbiased Molecular Characterization of Peripartum Cardiomyopathy Hearts Identifies Mast Cell Chymase as a New Diagnostic Candidate

TL;DR

This study identifies mast cell chymase as a potential diagnostic biomarker for peripartum cardiomyopathy using advanced molecular techniques.

Contribution

The study introduces chymase as a novel, specific diagnostic candidate for peripartum cardiomyopathy.

Findings

Mast cell proteins chymase and carboxypeptidase A3 are uniquely upregulated in PPCM hearts.

Chymase shows superior diagnostic performance in blood serum compared to NT-proBNP.

Mast cells are spatially localized near cardiac fibroblasts in PPCM tissue.

Abstract

Peripartum cardiomyopathy (PPCM) is a rare form of acute heart failure that develops in women toward the end of pregnancy or early postpartum. No effective, specific treatment for PPCM is available and heart transplantation or mechanical circulatory support may be required in severe cases where drug treatment for heart failure is insufficient. The mechanisms through which the disease progresses are not well understood, and despite similar clinical characteristics to dilated cardiomyopathy of other etiologies (nonperipartum cardiomyopathy; NPCM) it is not known how the molecular remodeling differs between these groups. We aimed to provide insight into the human PPCM heart using unbiased methodologies, and to use changes occurring within the heart tissue to facilitate biomarker discovery. We obtained heart tissue from female patients with end-stage disease receiving either heart transplantation or left ventricular assist device implantation, or from organ donors without heart disease as a control group. We performed deep proteomics, single nucleus transcriptomics and spatial transcriptomics, providing a comprehensive map of the molecular phenotype in advanced PPCM compared to both control and NPCM hearts. Consistent with similarities in the clinical phenotypes of PPCM and NPCM, we observed regulation of canonical markers of end-stage heart failure in both PPCM and NPCM hearts in comparison to controls. Among the changes specific to PPCM and that were consistently observed across multiple data types and cohorts was an upregulation of chymase and carboxypeptidase A3, consistent with mast cell proliferation/activation. Analysis of the proteome of peripheral blood serum from a larger cohort of patients with PPCM and controls showed that chymase was strongly predictive of cardiomyopathy in peripartum women. PPCM heart tissue is characterized by increased mast cell proteins chymase and carboxypeptidase A3. Chymase may have clinical utility as a biomarker for the diagnosis of cardiomyopathy in peripartum women.

•Peripartum cardiomyopathy heart tissue: proteomics, snRNAseq & spatial RNAseq.•Mast cell proteins CMA1 & CPA3 specifically upregulated in peripartum cardiomyopathy.•Validation using bulk RNAseq from a published external cohort.•Mast cells spatially localize in proximity to cardiac fibroblasts.•Superior diagnostic performance of chymase compared to NT-proBNP in blood serum.

Peripartum cardiomyopathy heart tissue: proteomics, snRNAseq & spatial RNAseq.

Mast cell proteins CMA1 & CPA3 specifically upregulated in peripartum cardiomyopathy.

Validation using bulk RNAseq from a published external cohort.

Mast cells spatially localize in proximity to cardiac fibroblasts.

Superior diagnostic performance of chymase compared to NT-proBNP in blood serum.

Peripartum cardiomyopathy (PPCM) is a rare and poorly understood form of pregnancy-associated heart failure. Using deep proteomics alongside single-nucleus and spatial transcriptomics, we mapped the molecular landscape of human PPCM hearts and found mast cell proteins chymase and carboxypeptidase A3 uniquely elevated compared to nonperipartum cardiomyopathies. Independent blood serum analyses confirmed chymase as a predictor of PPCM, underscoring its potential as a diagnostic biomarker for peripartum cardiomyopathy.

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