Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure

Shangjie Zou; Bee Luan Khoo

doi:10.3389/fimmu.2023.1053793

Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure

Shangjie Zou
, Bee Luan Khoo^*

^*Corresponding author for this work

Department of Biomedical Engineering

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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Abstract

Background: A central issue hindering the development of effective anti-fibrosis drugs for heart failure is the unclear interrelationship between fibrosis and the immune cells. This study aims at providing precise subtyping of heart failure based on immune cell fractions, elaborating their differences in fibrotic mechanisms, and proposing a biomarker panel for evaluating intrinsic features of patients’ physiological statuses through subtype classification, thereby promoting the precision medicine for cardiac fibrosis.

Methods: We inferred immune cell type abundance of the ventricular samples by a computational method (CIBERSORTx) based on ventricular tissue samples from 103 patients with heart failure, and applied K-means clustering to divide patients into two subtypes based on their immune cell type abundance. We also designed a novel analytic strategy: Large-Scale Functional Score and Association Analysis (LAFSAA), to study fibrotic mechanisms in the two subtypes.

Results: Two subtypes of immune cell fractions: pro-inflammatory and pro-remodeling subtypes, were identified. LAFSAA identified 11 subtype-specific pro-fibrotic functional gene sets as the basis for personalised targeted treatments. Based on feature selection, a 30-gene biomarker panel (ImmunCard30) established for diagnosing patient subtypes achieved high classification performance, with the area under the receiver operator characteristic curve corresponding to 0.954 and 0.803 for the discovery and validation sets, respectively.

Conclusion: Patients with the two subtypes of cardiac immune cell fractions were likely having different fibrotic mechanisms. Patients’ subtypes can be predicted based on the ImmunCard30 biomarker panel. We envision that our unique stratification strategy revealed in this study will unravel advance diagnostic techniques for personalised anti-fibrotic therapy.

Original language	English
Article number	1053793
Journal	Frontiers in Immunology
Volume	14
Online published	15 Feb 2023
DOIs	https://doi.org/10.3389/fimmu.2023.1053793
Publication status	Published - 2023

Funding

This work was supported in part by InnoHK Project on [Project 1-2 - Design of DDS system structure and selection of potential drugs for acute CVDs] and [Project 1-5 Multi-modal spectroscopy (MMS) & biosensor platforms for monitoring CVDs] at Hong Kong Centre for Cerebro-cardiovascular Health Engineering (COCHE), in part by City University of Hong Kong (9610430, 7020002, 7005464, 7005208, 9667220), which is funded by the Research Grants Council (RGC), in part by Pneumoconiosis Compensation Fund Board (9211276), and in part by Research Grants Council (RGC 9048206). The views expressed are those of the authors and not necessarily those of InnoHK - ITC, City University of Hong Kong, Pneumoconiosis Compensation Fund Board, or Research Grants Council.

Research Keywords

heart failure
cardiac fibrosis
immune cell fractions
subtyping
functional gene sets

Publisher's Copyright Statement

This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

RGC Funding Information

RGC-funded

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10.3389/fimmu.2023.1053793

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ECS: Microfluidic Inflammatory Tumor Model for Drug Discovery in Patients with Systemic Infection
KHOO, B. L. (Principal Investigator / Project Coordinator)
1/01/22 → 5/06/26
Project: Research
HKgovt: Enrichment of Epithelial Mesothelioma Cell Clusters for Early Detection and Routine Monitoring of Patients Using Liquid Biopsy
KHOO, B. L. (Principal Investigator / Project Coordinator) & SUN, D. (Co-Principal Investigator)
1/08/21 → 28/02/25
Project: Research

Cite this

@article{85121ac2add1492ead74f3a9e192d500,

title = "Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure",

abstract = "Background: A central issue hindering the development of effective anti-fibrosis drugs for heart failure is the unclear interrelationship between fibrosis and the immune cells. This study aims at providing precise subtyping of heart failure based on immune cell fractions, elaborating their differences in fibrotic mechanisms, and proposing a biomarker panel for evaluating intrinsic features of patients{\textquoteright} physiological statuses through subtype classification, thereby promoting the precision medicine for cardiac fibrosis. Methods: We inferred immune cell type abundance of the ventricular samples by a computational method (CIBERSORTx) based on ventricular tissue samples from 103 patients with heart failure, and applied K-means clustering to divide patients into two subtypes based on their immune cell type abundance. We also designed a novel analytic strategy: Large-Scale Functional Score and Association Analysis (LAFSAA), to study fibrotic mechanisms in the two subtypes. Results: Two subtypes of immune cell fractions: pro-inflammatory and pro-remodeling subtypes, were identified. LAFSAA identified 11 subtype-specific pro-fibrotic functional gene sets as the basis for personalised targeted treatments. Based on feature selection, a 30-gene biomarker panel (ImmunCard30) established for diagnosing patient subtypes achieved high classification performance, with the area under the receiver operator characteristic curve corresponding to 0.954 and 0.803 for the discovery and validation sets, respectively. Conclusion: Patients with the two subtypes of cardiac immune cell fractions were likely having different fibrotic mechanisms. Patients{\textquoteright} subtypes can be predicted based on the ImmunCard30 biomarker panel. We envision that our unique stratification strategy revealed in this study will unravel advance diagnostic techniques for personalised anti-fibrotic therapy.",

keywords = "heart failure, cardiac fibrosis, immune cell fractions, subtyping, functional gene sets",

author = "Shangjie Zou and Khoo, \{Bee Luan\}",

year = "2023",

doi = "10.3389/fimmu.2023.1053793",

language = "English",

volume = "14",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Media S.A.",

}

TY - JOUR

T1 - Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure

AU - Zou, Shangjie

AU - Khoo, Bee Luan

PY - 2023

Y1 - 2023

N2 - Background: A central issue hindering the development of effective anti-fibrosis drugs for heart failure is the unclear interrelationship between fibrosis and the immune cells. This study aims at providing precise subtyping of heart failure based on immune cell fractions, elaborating their differences in fibrotic mechanisms, and proposing a biomarker panel for evaluating intrinsic features of patients’ physiological statuses through subtype classification, thereby promoting the precision medicine for cardiac fibrosis. Methods: We inferred immune cell type abundance of the ventricular samples by a computational method (CIBERSORTx) based on ventricular tissue samples from 103 patients with heart failure, and applied K-means clustering to divide patients into two subtypes based on their immune cell type abundance. We also designed a novel analytic strategy: Large-Scale Functional Score and Association Analysis (LAFSAA), to study fibrotic mechanisms in the two subtypes. Results: Two subtypes of immune cell fractions: pro-inflammatory and pro-remodeling subtypes, were identified. LAFSAA identified 11 subtype-specific pro-fibrotic functional gene sets as the basis for personalised targeted treatments. Based on feature selection, a 30-gene biomarker panel (ImmunCard30) established for diagnosing patient subtypes achieved high classification performance, with the area under the receiver operator characteristic curve corresponding to 0.954 and 0.803 for the discovery and validation sets, respectively. Conclusion: Patients with the two subtypes of cardiac immune cell fractions were likely having different fibrotic mechanisms. Patients’ subtypes can be predicted based on the ImmunCard30 biomarker panel. We envision that our unique stratification strategy revealed in this study will unravel advance diagnostic techniques for personalised anti-fibrotic therapy.

AB - Background: A central issue hindering the development of effective anti-fibrosis drugs for heart failure is the unclear interrelationship between fibrosis and the immune cells. This study aims at providing precise subtyping of heart failure based on immune cell fractions, elaborating their differences in fibrotic mechanisms, and proposing a biomarker panel for evaluating intrinsic features of patients’ physiological statuses through subtype classification, thereby promoting the precision medicine for cardiac fibrosis. Methods: We inferred immune cell type abundance of the ventricular samples by a computational method (CIBERSORTx) based on ventricular tissue samples from 103 patients with heart failure, and applied K-means clustering to divide patients into two subtypes based on their immune cell type abundance. We also designed a novel analytic strategy: Large-Scale Functional Score and Association Analysis (LAFSAA), to study fibrotic mechanisms in the two subtypes. Results: Two subtypes of immune cell fractions: pro-inflammatory and pro-remodeling subtypes, were identified. LAFSAA identified 11 subtype-specific pro-fibrotic functional gene sets as the basis for personalised targeted treatments. Based on feature selection, a 30-gene biomarker panel (ImmunCard30) established for diagnosing patient subtypes achieved high classification performance, with the area under the receiver operator characteristic curve corresponding to 0.954 and 0.803 for the discovery and validation sets, respectively. Conclusion: Patients with the two subtypes of cardiac immune cell fractions were likely having different fibrotic mechanisms. Patients’ subtypes can be predicted based on the ImmunCard30 biomarker panel. We envision that our unique stratification strategy revealed in this study will unravel advance diagnostic techniques for personalised anti-fibrotic therapy.

KW - heart failure

KW - cardiac fibrosis

KW - immune cell fractions

KW - subtyping

KW - functional gene sets

U2 - 10.3389/fimmu.2023.1053793

DO - 10.3389/fimmu.2023.1053793

M3 - RGC 21 - Publication in refereed journal

C2 - 36875078

SN - 1664-3224

VL - 14

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 1053793

ER -

Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

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Projects

ECS: Microfluidic Inflammatory Tumor Model for Drug Discovery in Patients with Systemic Infection

HKgovt: Enrichment of Epithelial Mesothelioma Cell Clusters for Early Detection and Routine Monitoring of Patients Using Liquid Biopsy

Cite this