Kidus Dube

Background:  Heart failure is one of the most common diseases in the United States with estimated direct costs of $39 billion to $60 billion each year.¹The disease is associated with a poor prognosis with a 50% mortality rate in the next 5 years after diagnosis requiring new treatments that can provide patients with a better prognosis.² One possible treatment that is being studied includes microRNA which are a class of  non-coding RNA that can alter gene function through multiple mechanisms such as blocking elongation of DNA or forcing termination of translation of a protein.³ Because of microRNA’s role in orchestrating the levels of cardiac gene expression, it can attenuate the progression of heart failure.

Objective:  In this narrative review, we studied the role of three microRNA’s in coordinating cardiac remodeling, cardiac hypertrophy, and fibrosis and how using them as a promising target can decelerate the process of heart failure.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the following keywords: “microRNA”, “heart failure”, “developmental cell”, and “genes and development”.

Results: For the first target, microRNA-1, knockdown (KD) of the microRNA in mice lead to a decreased expression by 25% of wild-type microRNA-1 in mice.⁴ Echocardiography revealed a significantly reduced ejection fraction in the 75% KD mice of 43.9% compared to the wild-type of 60.9%.⁴ Fractional shortening was also significantly reduced to 18.4% in 75% KD mice compared to 28.1% in wild-type.⁴ However, there were no significant differences in fibrosis.⁴ Treatment with microRNA-1 in microRNA-1 deficient hearts led to improved contractility but did decrease not the risk of arrhythmia development.⁴ For the second target, microRNA-152, overexpression lead to systolic dysfunction and dilated cardiomyopathy while pharmacological inhibition lead to improved cardiac function.⁵ The last microRNA, MicroRNA-30d, targets MAP4K4 which plays a role in death of cardiomyocytes.⁶ This microRNA is also secreted by cardiomyocytes to silence integrin alpha-5  to decrease fibrosis, thus, overexpression of microRNA-30d was associated with better cardiac remodeling in cardiomyocytes and decreased level of fibrosis.⁶ Ventricular function was also significantly improved in miR-30d overexpressing rats as compared to wild-type rats 3 weeks after a myocardial infarction.⁶ The first micro-RNA silencing study in a human found that microRNA-132 inhibition through CDR132L, a synthetic oligonucleotide, lead to decreased BNP levels, narrowed QRS complexes, and increased ejection fractions with toxicity. ⁷

Conclusion: As the burden of heart failure in the U.S. increases, new therapeutic treatment must be developed that targets cardiac remodeling. Diagnostic and therapeutic capabilities are currently limited for heart failure despite being the number one cause of cardiovascular disease morbidity and mortality². As research continues, the idea of microRNAs as a therapeutic target for heart failure provides many potential points of regulation.

Works Cited

1.  Heidenreich, P. A., Fonarow, G. C., Opsha, Y., Sandhu, A. T., Sweitzer, N. K., Warraich, H. J., & HFSA Scientific Statement Committee Members Chair (2022). Economic Issues in Heart Failure in the United States. Journal of cardiac failure, 28(3), 453–466. https://doi.org/10.1016/j.cardfail.2021.12.017
2. Roger V. L. (2021). Epidemiology of Heart Failure: A Contemporary Perspective. Circulation research, 128(10), 1421–1434. https://doi.org/10.1161/CIRCRESAHA.121.318172
3. Zhou, H., Tang, W., Yang, J., Peng, J., Guo, J., & Fan, C. (2021). MicroRNA-Related Strategies to Improve Cardiac Function in Heart Failure. Frontiers in cardiovascular medicine, 8, 773083. https://doi.org/10.3389/fcvm.2021.773083
4. Yang D, Wan X, Schwieterman N, et al. MicroRNA-1 Deficiency Is a Primary Etiological Factor Disrupting Cardiac Contractility and Electrophysiological Homeostasis. Circ Arrhythm Electrophysiol. 2024;17(1):e012150. doi:10.1161/CIRCEP.123.012150
5. LaRocca TJ, Seeger T, Prado M, et al. Pharmacological Silencing of MicroRNA-152 Prevents Pressure Overload-Induced Heart Failure. Circ Heart Fail. 2020;13(3):e006298. doi:10.1161/CIRCHEARTFAILURE.119.006298
6. Li J, Salvador AM, Li G, et al. Mir-30d Regulates Cardiac Remodeling by Intracellular and Paracrine Signaling. Circ Res. 2021;128(1):e1-e23. doi:10.1161/CIRCRESAHA.120.317244
7. Täubel, J., Hauke, W., Rump, S., Viereck, J., Batkai, S., Poetzsch, J., Rode, L., Weigt, H., Genschel, C., Lorch, U., Theek, C., Levin, A. A., Bauersachs, J., Solomon, S. D., & Thum, T. (2021). Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study. European heart journal, 42(2), 178–188. https://doi.org/10.1093/eurheartj/ehaa898