Heart Failure Promotes Multimorbidity Through Innate Immune Memory

Heart Failure Promotes Multimorbidity through Innate Immune Memory

Background Introduction

Heart failure (HF) is a common and fatal disease. Despite continuous advancements in medical technology, the mortality rate of heart failure remains high. HF patients frequently experience recurrent acute decompensation, which not only leads to the continuous deterioration of cardiac function but also makes them prone to developing multiple comorbidities such as chronic kidney disease and frailty syndrome. The pathological mechanisms underlying these comorbidities are complex and not fully understood. Recent studies have shown that innate immune memory plays a significant role not only in anti-infection responses but also in the development of non-communicable diseases.

Research Objective and Author Information

This study was jointly conducted by researchers from several renowned academic institutions, including the University of Tokyo, University of British Columbia, Kyoto University, and Chiba University. Key authors include Yukiteru Nakayama, Katsuhito Fujiu, Tsukasa Oshima, among others. The findings were published in the journal “Science Immunology” on May 24, 2024.

The primary aim of the study is to explore whether heart failure alters the function of hematopoietic stem cells (Hematopoietic Stem Cells, HSCs), leading to cardiac dysfunction and affecting other organs such as kidneys and skeletal muscles. The researchers hypothesize that heart failure may regulate the epigenome of HSCs, thereby altering their ability to generate cardiac macrophages. This change could be a key driving force behind recurrent HF events and multimorbidity.

Research Process

Experimental Design

  1. Establishing the Heart Failure Model: The research team induced heart failure in mice through transverse aortic constriction (TAC) and extracted bone marrow (BM) cells from these HF mice four weeks later.

  2. Bone Marrow Transplantation: Bone marrow cells extracted from HF mice and control mice were transplanted into young, lethally irradiated but otherwise healthy mice. Cardiac function and fibrosis were assessed four months later.

  3. Competitive Transplantation of HSCs: Using different labeled mice, the research team performed competitive transplantation of HSCs to assess the impact of cardiac pressure overload on the differentiation potential of HSCs.

  4. Gene Expression and Epigenome Analysis: RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) were employed to analyze gene expression changes in HSCs and their derived macrophages from HF mice. Chromatin accessibility sequencing (ATAC-seq) was used to assess epigenomic changes.

Main Experimental Results

  1. Cardiac Dysfunction: Mice transplanted with bone marrow cells from HF mice showed significant deterioration in cardiac function and increased fibrosis.

  2. Altered Differentiation Potential of HSCs: HSCs from TAC-treated mice exhibited a greater tendency to generate CCR2+ macrophages rather than tissue-resident CCR2- macrophages, indicating that cardiac pressure overload altered the differentiation pathway of HSCs.

  3. Changes in Epigenome and Gene Expression: HSCs from HF mice displayed significant changes in gene expression and chromatin accessibility, particularly the inhibition of the TGF-β signaling pathway.

  4. Multiorgan Vulnerability: Mice transplanted with HSCs from HF mice showed more severe pathological changes in the kidneys and skeletal muscles upon injury, indicating that HF not only affects cardiac function but also increases the vulnerability of other organs through changes in HSCs.

Research Conclusion

This study reveals that heart failure regulates the epigenome of HSCs, altering their ability to generate inflammatory macrophages, thereby causing pathological changes in the heart and other organs. This discovery provides new insights into the understanding of heart failure and its associated comorbidities and may offer new targets for future therapeutic strategies.

Research Significance

Scientific Value

  1. Revealing New Mechanisms: The study elucidates how cardiac pressure overload influences the epigenome of hematopoietic stem cells, causing pathological changes in the heart and other organs, offering a new understanding of the mechanisms of heart failure and multimorbidity.

  2. Extension of Innate Immune Memory: The research finds that HSCs carry “stress memory” after cardiac pressure overload, expanding the role of innate immune memory in non-communicable diseases and proposing new research directions.

Application Value

  1. New Therapeutic Targets: The study suggests that regulating HSCs and the subpopulations of macrophages they generate could be a new strategy for treating heart failure and its related comorbidities.

  2. Multiorgan Protection: By understanding the role of HSCs in heart failure, future therapeutic approaches could not only target the heart but also consider the protection of other organs such as kidneys and skeletal muscles, providing comprehensive treatment plans.

Research Highlights

  1. “Stress Memory” of HSCs: The study is the first to propose that HSCs carry “stress memory” after cardiac pressure overload and demonstrates how this memory can change the generation of macrophages, leading to pathological changes in multiple organs.

  2. Epigenomic Changes: Through RNA-seq and ATAC-seq technologies, the study meticulously demonstrates the impact of cardiac pressure overload on the gene expression and chromatin accessibility of HSCs, providing an in-depth analysis of molecular mechanisms.

  3. Multiorgan Vulnerability: The research evaluates not only cardiac function but also the extent of damage to kidneys and skeletal muscles after cardiac pressure overload, proposing a new mechanism for heart failure-induced multimorbidity.

Future Outlook

This study provides new insights into the understanding of heart failure and its associated comorbidities but also raises many questions that require further investigation. For example, how exactly does cardiac pressure overload regulate the epigenome of HSCs? Which signaling pathways play key roles in this process? Answers to these questions will provide more theoretical support and application prospects for the treatment of heart failure. In the future, researchers can also explore how to intervene in the changes in HSCs to develop new therapeutic methods, effectively addressing heart failure and its related comorbidities, and improving patients’ quality of life.