Madeline Jordan

Background: Heart failure currently affects 6 million people in the United States comprising almost two percent of the population². Patients with severe heart failure experience great inability to carry out physical activity leaving patients nearly bed bound with high rates of mortality³. Current treatments focus on supportive therapies to mitigate the symptoms of heart failure, but no cure outside of heart transplants currently exists^4,5. Eighty percent of all people with heart failure are classified as geriatric leading researchers to investigate potential epigenetic mutations related to aging that may be contributing to this increase prevalence of heart failure^1,3,6. One such epigenetic mutation is DNA methyltransferase 3 alpha (DNMT3A), which is a driver mutation leading to the development of clonal hematopoiesis of indeterminate potential (CHIP), a condition that shares a high correlation with heart failure in geriatric populations^1,3,7. Since 50% of the geriatric population has CHIP, discovering the mechanism connecting CHIP and heart failure can open up the potential for developing curative therapeutic interventions^3,7.

Objective: In this review, the mechanism between heart failure and CHIP mutations caused by DNTM3A was explored via various in vivo and in vitro experimental studies.

Search Methods: Within the PubMed database, in the time frame of 2018-2024, the following key words were used: “heart failure”, “CHIP”, “epigenetics”, “DNMT3A”, “cardiac fibrosis”.

Results: In a 200-patient clinical study, patients showed statistically significant correlation between heart failure and a CHIP inducing mutation with 16% of mutations silencing the methylation regulator protein DNMT3A⁸. DNMT3A was causally proven to contribute to cardiac fibrotic tissue in mice models via inflammation attributed to cytokines including Cxcl1, Cxcl2, and IL-6 found in the cardiac tissue⁹. Using Cell-Chat technology, DNMT3A mutated CHIP monocytes had the highest amount of “communication” with cardiac fibroblasts that was statistically significant from non-mutated monocytes¹. When combined in solution with cardiac fibroblasts, increased levels of -smooth muscle actin (SMA), a known marker of fibroblast activation, and TGF-β1, a fibrinogenic factor found in cardiac tissue were found. These fibroblasts also exhibited increased collagen expression and visible contraction demonstrating the ability of DNMT3A mutated monocyte’s ability to activate cardiac fibroblasts¹. When cardiac mimetic tissue, “cardiospheres”, were treated with DNMT3A monocytes, they exhibited an increased percentage of fibrotic tissue and reduced contractility mimicking a restrictive cardiomyopathy that could contribute to heart failure¹. Epidermal growth factor was measured to be the chemical of highest signal flow between DNMT3A mutated monocytes and cardiac fibroblasts with heparin binding epidermal growth factor (HB-EGF) being found at elevated rates in the plasma of patients with heart failure¹.

Conclusion: Studies have found that silencing mutations of DNTM3A leading to CHIP have a high correlation with cardiac tissue inflammation, fibrosis, and heart failure^1,3,7. DNMT3A mutated monocytes are shown to activate fibroblasts in cardiac tissue via HB-EGF providing grounds for a mechanism of diffuse fibrosis in the heart leading to reduction in heart contractility and development of heart failure in geriatric populations with this mutation¹.

 Works Cited: 

1. Shumliakivska M, Luxán G, Hemmerling I, et al. DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts. Nat Commun. 2024;15(1):606. Published 2024 Jan 19. doi:10.1038/s41467-023-43003-w
2. Roger VL. Epidemiology of Heart Failure: A Contemporary Perspective. Circ Res. 2021;128(10):1421-1434. doi:10.1161/CIRCRESAHA.121.318172
3. Chen J, Aronowitz P. Congestive Heart Failure. Med Clin North Am. 2022;106(3):447-458. doi:10.1016/j.mcna.2021.12.002
4. Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart Failure With Reduced Ejection Fraction: A Review [published correction appears in JAMA. 2020 Nov 24;324(20):2107]. JAMA. 2020;324(5):488-504. doi:10.1001/jama.2020.10262
5. Mohamed MO. Prevention is better than cure: modifiable risk factors for heart failure better understood. Eur J Heart Fail. 2022;24(3):481-482. doi:10.1002/ejhf.2448
6. Triposkiadis F, Xanthopoulos A, Parissis J, Butler J, Farmakis D. Pathogenesis of chronic heart failure: cardiovascular aging, risk factors, comorbidities, and disease modifiers. Heart Fail Rev. 2022;27(1):337-344. doi:10.1007/s10741-020-09987-z
7. Jaiswal S, Libby P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease [published correction appears in Nat Rev Cardiol. 2020 Dec;17(12):828]. Nat Rev Cardiol. 2020;17(3):137-144. doi:10.1038/s41569-019-0247-5
8. Dorsheimer L, Assmus B, Rasper T, et al. Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure. JAMA Cardiol. 2019;4(1):25-33. doi:10.1001/jamacardio.2018.3965
9. Sano S, Oshima K, Wang Y, Katanasaka Y, Sano M, Walsh K. CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease. Circ Res. 2018;123(3):335-341. doi:10.1161/CIRCRESAHA.118.313225