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Clonal Hematopoiesis: The Somatic Risk Factor Hiding in Plain Sight

Article

June 17, 2026

Clonal Hematopoiesis: The Somatic Risk Factor Hiding in Plain Sight

When US President Dwight D. Eisenhower suffered a heart attack in 1955, the event shocked the American public [1]. Though smoking was common, the biological links between tobacco and cardiovascular disease were only beginning to enter mainstream medical discussion.


Today, the connection feels obvious.


Clonal hematopoiesis (CH) may occupy a similar position in medicine today: increasingly well studied, biologically consequential, and still unfamiliar to most patients and physicians alike. In some populations it even carries a similar cardiovascular risk as smoking [2].


Cardiovascular disease is the leading cause of death globally, accounting for nearly 1 in 3 deaths worldwide [3]. Yet over 1 in 5 patients with heart attacks or strokes present without traditional cardiovascular risk factors [4,5]. Increasingly, evidence suggests that some of those events may begin years earlier in the bone marrow.


A Mutation That Expands With Age


Clonal hematopoiesis (CH) is a condition that becomes increasingly common with age. It emerges as early as age 40 [6], and detectable clones are found in up to 62% of people above age 80 [7].


CH starts in the blood stem cells, which function like the body's blood cell "factories." Over time, some acquire somatic mutations that allow them to outcompete neighboring cells. As that mutated clone expands, a growing proportion of circulating blood cells descend from the same altered stem cell.


Studies on mice have shown that immune cells with a TET2 mutation produce inflammatory cytokines that accelerate atherosclerotic plaque formation [8,9]. JAK2-mutant clones have been linked to pro-thrombotic signaling and platelet activation [10].


These processes may begin years before routine blood counts show any abnormalities.


An Early Signal of Leukemia and Cardiovascular Risk


Hematologists have recognized for years that leukemia-associated mutations can appear long before overt malignancy develops. A landmark study published in the New England Journal of Medicine (NEJM) reported up to a 12.9× increased relative risk of hematologic malignancy in individuals with CH compared with the general population [11].


Individuals with CH carry elevated risk of progression toward blood disorders characterized by lower blood counts, abnormal blood cell development, and eventually leukemia, particularly at higher clone sizes and with certain mutation profiles [12].


The Cardiovascular Connection


Over the past decade, the same mutations linked to leukemia also emerged as contributors to cardiovascular disease.


In landmark studies published in NEJM, CH was associated with up to 12× increased risk of heart attack [9] and 3.1× increased risk of stroke [5], even in patients without traditional cardiovascular risk factors.


Increasingly, CH appears to sit early in the cardiovascular disease timeline, potentially contributing to arterial inflammation years before heart attack or stroke occur.


Figure 1. Clonal Hematopoiesis Testing May Reveal Cardiovascular Risk Before It Becomes Arterial Damage
Figure 1. Clonal Hematopoiesis Testing May Reveal Cardiovascular Risk Before It Becomes Arterial Damage

From Research Concept to Clinical Discussion


In his recent blog post entitled "The Missing CHIP", cardiologist Dr. Eric Topol draws parallels to the clinical adoption of Lp(a) and ApoB, citing that it took 8 years for guidelines to align with the body of evidence supporting these lipid panels [17].


CH may be approaching a similar inflection point. The American Heart Association recently stated that "CH is increasingly recognized as a potential driver of CVD" [18].


Sequencing technologies are becoming more accessible, larger longitudinal datasets are emerging, and evidence continues to accumulate linking CH to both cardiovascular disease and blood cancers.


Clinical management is also evolving. Though no therapy is currently approved specifically to target CH itself, early studies suggest that anti-inflammatory medications,[19,20] lipid-lowering medications [21], and weight loss interventions [22,23] may slow down CH clonal expansion and potentially mitigate downstream health risk.


As evidence continues to grow, CH screening may help explain part of the persistent gap in cardiovascular risk prediction, including the substantial proportion of heart attacks and strokes that still occur without traditional risk factors.


References:


  1. Lee T. N Engl J Med 2020;383(18):e100. doi:10.1056/NEJMp2031046

  2. Jaiswal S and Ebert B. Science 2019;366(6465):eaan4673. doi:10.1126/science.aan4673

  3. World Health Organization. Cardiovascular diseases (CVDs). World Health Organization. Updated June 11, 2021. Accessed May 28, 2026. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

  4. Paul G, et al. Global Heart 2023;18(1). doi:10.5334/gh.1189

  5. Beharry J, et al. Eur Stroke J 2025. doi:10.1177/23969873241309516

  6. Jaiswal S, et al. N Engl J Med 2014;371(26):2488–2498. doi:10.1056/NEJMoa1408617

  7. van Zeventer I, et al. Blood Adv 2021;5(8):2115–2122. https://doi.org/10.1182/bloodadvances.2020004062

  8. Rauch P, et al. Blood 2018;132 Supp 1:745. https://doi.org/10.1182/blood-2018-99-118288.

  9. Jaiswal S, et al. N Engl J Med 2017;377:111–121. doi:10.1056/NEJMoa1701719

  10. Liu W, et al. Blood 2023;143(15):1539–1550. doi:10.1182/blood.2023022260.

  11. Genovese G, et al. N Engl J Med 2014;371:2477–2487.

  12. Sperling A, et al. Nat Rev Cancer 2017;17:5–19. doi:https://doi.org/10.1038/nrc.2016.112

  13. Nordestgaard BM, et al. Eur Heart J 2010;31(23):2844–2853. doi:10.1093/eurheartj/ehq386.

  14. Sniderman A, et al. JAMA Cardiol 2022;7(3):257–258. doi:10.1001/jamacardio.2021.5080.

  15. Ridker P. Am Heart J 2004;148(1 Suppl):S19–26. doi:10.1016/j.ahj.2004.04.028.

  16. Nasir K and Cainzos-Achirica M. BMJ 2021:373:n776. doi:10.1136/bmj.n776.

  17. Topol E. The Missing Chip. Ground Truths. Published January 19, 2025. Accessed May 27, 2026. https://erictopol.substack.com/p/the-missing-chip

  18. Rhee J-W, et al. Circulation 2026;153(11):https://doi.org/10.1161/CIR.0000000000001404

  19. Mohammadnia N, et al. J Am Coll Cardiol 2025 Nov 25;86(21):1983–1996. doi:10.1016/j.jacc.2025.08.025.

  20. Tardif J-C, et al. Circulation 2026;153(8):610–612. https://doi.org/10.1161/CIRCULATIONAHA.125.077665

  21. Musson E, et al. Blood 2024;144(Supp1):1283. https://doi.org/10.1182/blood-2024-203136

  22. Orland M, et al. Blood 2025;146(Supp 1):1385. https://doi.org/10.1182/blood-2025-1385

  23. Andersson-Assarsson J, et al. EBioMedicine 2023;92:104621. doi:10.1016/j.ebiom.2023.104621.

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