Priya Modi

Background: Heart failure (HF) is a chronic progressive syndrome affecting more than six million adults in the United States and is associated with significant morbidity, mortality, and healthcare costs.¹ Current guideline-directed medical therapies improve survival by targeting neurohormonal pathways but do not directly address the underlying molecular drivers of cardiac remodeling.² Pathologic remodeling in HF involves cardiomyocyte hypertrophy, fibrosis, mitochondrial dysfunction, inflammation, and impaired contractility. Recent studies have identified RNA-based regulation, particularly N⁶-methyladenosine (m6A) RNA methylation, as a major contributor to these processes.³ m6A is the most abundant internal mRNA modification and functions as a dynamic, reversible regulator of post-transcriptional gene expression through writer, reader, and eraser proteins.³⁻⁵ Dysregulation of this pathway has been increasingly linked to maladaptive cardiac remodeling and progression of heart failure.

Objective: This narrative review examined the role of m6A RNA methylation in cardiac remodeling and evaluated the therapeutic potential of targeting m6A regulatory pathways in heart failure.

Search Methods: A literature search was conducted using the PubMed database for studies published between 2018 and 2025. Search terms included “heart failure,” “m6A methylation,” “METTL3,” “FTO,” “cardiac remodeling,” “cardiac hypertrophy,” “RNA therapeutics,” and “cardiomyocyte regeneration.” Primary mechanistic studies involving mouse models, RNA sequencing, m6A sequencing, echocardiography, and gene manipulation were emphasized.

Results: Multiple mechanistic studies demonstrated that abnormal m6A regulation contributes directly to pathologic cardiac remodeling. Dorn et al. showed that cardiomyocyte-specific METTL3 overexpression increased m6A methylation and promoted hypertrophic growth, while complete METTL3 knockout impaired stress adaptation and accelerated decompensated heart failure after pressure overload.⁵ These findings suggest that balanced m6A regulation is necessary for maintaining cardiac homeostasis. Kmietczyk et al. further demonstrated that m6A methylation patterns rapidly change during cardiac stress and dynamically regulate hypertrophic signaling pathways.⁶ Mathiyalagan et al. found that FTO, the primary cardiac m6A demethylase, decreases after myocardial infarction, resulting in abnormal m6A accumulation and reduced expression of key contractility genes such as SERCA2a and α-MHC.⁷ Restoration of FTO improved ejection fraction, normalized contractility-related gene expression, and reduced maladaptive remodeling in mouse models.⁷ Additional studies demonstrated that reduced FTO levels correlate with worsening hypertrophy, while FTO knockout exaggerates adverse remodeling after myocardial infarction.⁷ Magadum et al. also showed that RNA-based metabolic reprogramming through PKM2 activation promoted cardiomyocyte proliferation, reduced scar formation, and improved post-myocardial infarction cardiac function.⁸ Together, these findings demonstrate that m6A regulation controls multiple pathways involved in hypertrophy, contractility, stress adaptation, and cardiac repair.

Conclusions: m6A RNA methylation represents a promising new therapeutic target in heart failure. Both increased METTL3 activity and decreased FTO activity contribute to excess m6A accumulation and maladaptive cardiac remodeling. Importantly, the data suggest that maintaining physiologic m6A balance, rather than complete inhibition or activation, is essential for preserving cardiac function. Emerging therapies such as RNA-based therapeutics, small molecules, antisense oligonucleotides, and targeted gene delivery systems may allow more precise regulation of these pathways. Further studies are needed to validate these findings in human models and develop safe cardiac-specific delivery strategies for clinical use.

Works Cited

1. Deiman FE, de Graaf MM, Sillje HHW, et al. RNA therapeutics in heart failure. J Cardiovasc Transl Res. 2025;18(6):1540-1554. doi:10.1007/s12265-025-10717-9
2. Fan S, Hu Y. Role of m6A methylation in the occurrence and development of heart failure. Front Cardiovasc Med. 2022;9:892113. doi:10.3389/fcvm.2022.892113
3. Magadum A. Modified mRNA therapeutics for heart diseases. Int J Mol Sci. 2022;23(24):15514. doi:10.3390/ijms232415514
4. Deiman FE, de Graaf MM, Sillje HHW, et al. RNA therapeutics in heart failure. J Cardiovasc Transl Res. 2025;18(6):1540-1554. doi:10.1007/s12265-025-10717-9
5. 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
6. Kmietczyk V, Riechert E, Kalinski L, et al. m6A-mRNA methylation regulates cardiac gene expression and cellular growth. Life Sci Alliance. 2019;2(2):e201800233. doi:10.26508/lsa.201800233
7. 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
8. Magadum A, Singh N, Kurian AA, et al. Pkm2 regulates cardiomyocyte cell cycle and promotes cardiac regeneration. Circulation. 2020;141(15):1249-1265. doi:10.1161/CIRCULATIONAHA.119.043067