What is the clinical evidence from this study?

Study design: Observational. Population: Heart failure (n=33). Intervention: DNMT3A CHIP-driver mutations vs. No-CHIP. Primary outcome: Native T1 relaxation time (diffuse myocardial fibrosis) (p=0.0497).

January 19, 2024Open Access

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts

Key Result

DNMT3A CHIP-driver mutations in monocytes induce cardiac fibroblast activation and significantly increase diffuse myocardial fibrosis in heart failure patients.

Study Design

Type

Observational (n=33)

Structured PICO

Does DNMT3A clonal hematopoiesis-driver mutation induce cardiac fibrosis in heart failure models?

Population

Preclinical models including THP-1 monocytes, human cardiac fibroblasts, 3D cardiospheres, and humanized DNMT3A-R882H knock-in mice post-myocardial infarction, alongside human transcriptomic data from HFrEF patients with DNMT3A CHIP (n=5) vs No-CHIP (n=4), healthy heart tissue (n=14), and HFrEF tissue (n=3).

Intervention

DNMT3A inactivation or mutation (siRNA silencing in vitro, DNMT3A-R882H mutation in vivo via bone marrow transplantation)

Comparator

Wild-type or control (control siRNA in vitro, wild-type bone marrow cells in vivo, No-CHIP patients)

Outcome

Cardiac fibroblast activation and cardiac fibrosis (assessed via alpha-SMA expression, picrosirius red staining, and fibrotic gene expression)surrogate

DNMT3A clonal hematopoiesis-driver mutations promote heart failure progression by inducing paracrine activation of cardiac fibroblasts and exacerbating diffuse cardiac fibrosis.

Main Result

p-value: p=0.0497

Limitations

Causal contributions of the HB-EGF-EGF receptor interactions to cardiac fibrosis have only been documented through the use of in vitro models and cardiac tissue mimetics.
In silico prediction analysis is limited to the examination of interactions between circulating monocytes and human cardiac tissue.
Murine heart failure analysis was conducted in a model of ischemia-induced heart failure, while the clinical data originate from HFrEF patients, potentially with different underlying etiologies.

Abstract

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies.

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