# Methylated PIH1D1 as a Heart-Specific Biomarker for Anthracycline-Induced Cardiac Remodeling in Breast Cancer Patients

## TL;DR

This study identifies a new blood-based biomarker, methylated PIH1D1, that can detect early heart damage in breast cancer patients receiving anthracycline chemotherapy.

## Contribution

The discovery of methylated PIH1D1 as a heart-specific biomarker for early cardiac injury in anthracycline-treated patients.

## Key findings

- Over 50% of patients showed reduced left ventricular ejection fraction and ventricular dilation after anthracycline therapy.
- mPIH1D1 levels at 3-6 months predicted future ventricular dilation and LVEF decline with high accuracy.
- Combining cfDNA methylation with echocardiography improves early detection and management of cardiotoxicity.

## Abstract

•Anthracycline therapy induces early ventricular dilation and a decline in LVEF, reflecting subclinical remodeling toward dilated cardiomyopathy.•Circulating mPIH1D1 serves as a heart-specific cfDNA biomarker for early cardiac injury detection.•Elevated mPIH1D1 levels at 3 to 6 months predict subsequent ventricular dilation and LVEF reduction with high diagnostic accuracy.•Regimen analysis shows Lipo-DOX mitigates remodeling, whereas anthracycline + 5-FU aggravates dilation.•Integrating cfDNA methylation with echocardiography enables precision monitoring and early cardioprotection in cardio-oncology.

Anthracycline therapy induces early ventricular dilation and a decline in LVEF, reflecting subclinical remodeling toward dilated cardiomyopathy.

Circulating mPIH1D1 serves as a heart-specific cfDNA biomarker for early cardiac injury detection.

Elevated mPIH1D1 levels at 3 to 6 months predict subsequent ventricular dilation and LVEF reduction with high diagnostic accuracy.

Regimen analysis shows Lipo-DOX mitigates remodeling, whereas anthracycline + 5-FU aggravates dilation.

Integrating cfDNA methylation with echocardiography enables precision monitoring and early cardioprotection in cardio-oncology.

Anthracyclines, key chemotherapy agents, pose cardiotoxicity risks. In a 3-year study of 89 breast cancer patients treated with doxorubicin or epirubicin, more than 50% showed reduced left ventricular ejection fraction and progressive ventricular dilation. Although troponin-I flagged acute damage, it failed to predict long-term remodeling. Using a human methylome atlas, researchers identified 33 heart-specific methylated CpG sites and validated methylated PIH1D1 (mPIH1D1) as a novel biomarker. Elevated mPIH1D1 levels strongly correlated with ventricular dilation but not left ventricular ejection fraction decline, indicating its sensitivity to early cardiac remodeling. mPIH1D1 may complement troponin-I in risk assessment and cardiotoxicity management for patients undergoing anthracycline-based chemotherapy.