Developing a Systems Biology Map for Takotsubo Cardiomyopathy Insights into Neurohormonal and Sex Differences

Document Type

Conference Proceeding

Publication Date

4-2026

Publication Title

Journal of the American College of Cardiology

Abstract

Background: Takotsubo cardiomyopathy (TCM) is an acute stress-induced cardiomyopathy characterized by transient left ventricular dysfunction resulting from a catecholamine surge. TCM predominantly affects post-menopausal women, suggesting a protective role of estrogen through interactions with catecholamine receptors. The objective was to explore additional hormone-receptor contributors to TCM.

Methods: Adrenergic receptor beta-2 (ADRB2), estrogen receptors (ESR1/2), and the G-protein coupled estrogen receptor (GPER1) were identified from the literature. Gene lists for TCM were extracted from Open Targets Platform (OTP; ontology EFO_1002000), an integrated gene-to-disease atlas. Gene-hormone interaction analysis of OTP identified genes was conducted using the Comparative Toxicogenomics Database (CTDbase) with a focus on gene interactions with estrogen and estradiol. Further protein interactions were explored using STRING, the Genotype-Tissue Expression Project (GTEx), and the Chan Zuckerberg Initiative single-cell atlas (cellxgene).

Results: OTP identified 777 genes with potential involvement in TCM with an enrichment of genes for heart contraction, myocardial infarction, and adrenergic signaling. However, no score was significant, suggesting that TCM gene contributions are poorly linked. 13 of the TCM genes (OXT, ADCY9, ERBB2, AGTR1, NPY, ADRB2, ARRB1, ADRB1, GNAI2, RAPGEF4, EDN1, GRK5, CACNA1C) are associated with ADRB2 interaction and respond to estrogen/estradiol, with nine of these genes involved in G protein-coupled receptor biology. Broader analysis of non-OTP genes identified high PENK expression in left ventricular fibroblasts. Further single-cell analysis revealed notable sex-specific differences. PENK was detected in 0.04% of male ventricular cardiomyocytes (gene expression = 1.60; scaled expression = 0.10) compared with 4.7% in females (gene expression = 2.77; scaled expression = 0.71).

Conclusion: These findings suggest that multiple genes likely contribute to sex biases in TCM risk, highlighting a potential novel role for PENK. Further study of enkephalin-adrenergic interactions may clarify mechanisms and reveal therapeutic targets.

Volume

87

Issue

13 Suppl

First Page

A528

Comments

American College of Cardiology 75th Annual Scientific Session & Expo, March 28-30, 2026, New Orleans, LA

Last Page

A528

DOI

10.1016/j.jacc.2026.02.1427

ISSN

0735-1097

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