Tran Vu Phuong Nguyen

Background: Heart failure (HF) is a leading cause of mortality.¹ Characterized by its heterogenous etiological and complex profile, HF affects millions worldwide.¹ Despite its prevalence, no curative treatment for HF exists, and conventional genomics-targeted interventions have proved inadequate. Thus, there is a critical need for alternative avenues. Epitranscriptomic modifications, especially N⁶-methyladenosine (m6A) modifications of RNA, have recently emerged as a promising player in many systems, including cardiac.^2-4 m6A modification is the most ubiquitous and abundant RNA modification in eukaryotes, and global m6A modifications has been shown to be elevated in HF.⁵ Yet despite the evidence of m6A’s importance in HF, there exists few studies on 1) whether m6A truly plays a causative role in HF development, and if so, 2) how these m6A-modifying proteins precipitate this effect and whether this can be harnessed for therapeutic effect. These findings would be critical in

Objective: This review establishes the relevance of RNA m6A modifications in HF and how m6A “writer” (methylase) METTL3 and “eraser” (demethylase) FTO mechanistically leads to HF development and progression

Search Methods: A PubMed search using the following keywords were used: “RNA Processing, Post-Transcriptional”[Mesh], “m6A”, “METTL3”, or “FTO”. Each combination was proceeded by “AND heart” to restrict the results to heart and HF-related studies. Studies were restricted to those published within the last 7 years (2019-2025).

Results: Resulting studies indicated elevated global RNA m6A modifications in failing hearts of pig, murine, and human models.⁵ RNA-seq and MeRIP-seq (m6A-methylated RNA sequencing) analysis of failing human and murine cardiomyocytes (CMs) correlated m6A with dysregulated contractile function, cell plasticity. Functional analysis showed both human and murine models had downregulation of genes involved in cardiac contraction regulation via Ca²⁺ handling.⁷ Knockout of METTL3, a m6A writer, resulted in pathological (eccentric) remodeling and reduced cardiac function (i.e., reduced fractional shortening [FS] and left ventricular end-diastolic diameter [LVEDd]).⁷ Knockout of FTO, a m6A eraser, also resulted in pathological changes and diminished contractility; furthermore, FTO-knockdown (KD) also increased arrhythmic events in CMs.⁷ Conversely, FTO overexpression demonstrated cardiac rescue functions post-HF: OE models displayed restored cardiac function (increased FS and ejection fraction [EF].⁵ Mechanistically, FTO-OE in mice was correlated with restoration of SERCA2a, a Ca2+ handling protein, expression to normal protein levels–in contrast to its low levels observed in HF.⁵ FTO-OE also promoted glycolysis by promoting GLUT4 receptor expression.⁸

Conclusion: RNA m6A modifications causes progression to heart failure via dysregulation of cardiac architecture and activity. However, the role of m6A writers and erasers is complex: Knockdown of METTL3 (writer) and FTO (eraser) can both precipitate HF, albeit through potentially different genes. FTO, atop its role in normal cardiac function, also confers cardioprotective function when overexpressed, including resistance to hypoxia-induced arrhythmia and increased glycolytic function. Further investigation of m6A-modifying proteins, such as FTO, should be considered for future treatments in HF.

Works Cited:

1. Khan MS, Shahid I, Bennis A, Rakisheva A, Metra M, Butler J. Global epidemiology of heart failure. Nat Rev Cardiol. 2024;21(10):717-734. doi:10.1038/s41569-024-01046-6.
2. Wang C, Hou X, Guan Q, et al. RNA modification in cardiovascular disease: implications for therapeutic interventions. Signal Transduct Target Ther. 2023;8(1):412. Published 2023 Oct 27. doi:10.1038/s41392-023-01638-7.
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5. Mathiyalagan P, Adamiak M, Mayourian J, et al. FTO-Dependent N6-Methyladenosine Regulates Cardiac Function During Remodeling and Repair. Circulation. 2019;139(4):518-532. doi:10.1161/CIRCULATIONAHA.118.033794.
6. Dorn LE, Lasman L, Chen J, et al. The N6-Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy. Circulation. 2019;139(4):533-545. doi:10.1161/CIRCULATIONAHA.118.036146
7. Berulava T, Buchholz E, Elerdashvili V, et al. Changes in m6A RNA methylation contribute to heart failure progression by modulating translation. Eur J Heart Fail. 2020;22(1):54-66. doi:10.1002/ejhf.1672.
8. Zhang B, Jiang H, Wu J, et al. m6A demethylase FTO attenuates cardiac dysfunction by regulating glucose uptake and glycolysis in mice with pressure overload-induced heart failure. Signal Transduct Target Ther. 2021;6(1):377. Published 2021 Nov 2. doi:10.1038/s41392-021-00699-w.