Clonal Hematopoiesis: Cardiovascular and Clinical Implications
Daniel I. Nathan, MD
Assistant Professor, Hematology and Medical Oncology
Icahn School of Medicine at Mount Sinai
NYS Genetics Task Force
New Genomic Frontiers
June 4, 2025
Disclosures
Consulting for NeoGenomics.
Normal hematopoiesis
By A. Rad and M. Häggström. CC-BY-SA 3.0 license
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Clonal hematopoiesis
By A. Rad and M. Häggström. CC-BY-SA 3.0 license
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CH is a mutational processes of aging
“By age 70, an average person without a hematological cancer will harbor 350,000 to 1.4 million protein coding mutations in his or her HSC pool”
Jaiswal S and Ebert BL, Science 2019
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CH Taxonomy
Weeks LD and Ebert BL, Blood, 2023
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Risk for hematologic malignancy across all CH subtypes
Niroula A, et al. Nature Med., 2021
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CHIP: Clonal hematopoiesis of indeterminate potential
Figure courtesy of Myvizhi Esai Selvan
Steensma et al., Blood 2015
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Age
Peripheral blood
No somatic mutation
CHIP mutation
- Variant allele fraction >2%
- No hematologic disease
- Myeloid associated gene
Clone of mutant myeloid hematopoietic cells
Acquisition of somatic mutations
Normal myeloid hematopoietic cells
10-20% of population by age 70
Genetic landscape of CHIP is dominated by a few genes
Gu M, et al. Nature Genetics, 2023
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~80% of all genes are “DTA”
Most individuals have single mutation
The clinical spectrum of CHIP, CCUS, and malignancy
Figure created with BioRender.Com
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Hematologic Neoplasm
Development of cytopenia
CHIP
CCUS
Acquisition of additional mutations/ malignant transformation
Inflammation drives CHIP pathogenesis and morbidity
Figure courtesy of Lilas Armstrong-Davies. Please do not share without permission.
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CHIP is a risk factor for coronary heart disease
Jaiswal S, et al., Blood 2017
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CHIP is associated with pan-arterial atherosclerosis
Zekavat SM, et al. Nat Cardiovasc Res. 2023
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Tet2 KO promotes atherosclerosis via inflammation
Fuster JJ, et al. Science 2017
Figure created with BioRender.Com
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Longitudinal study of baseline CH on femoral plaque
Diez-Diez M, et al. Nature Med. 2024
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Atherosclerosis and CHIP: CHicken or Egg?
Sanchez-Cabo F & Fuster JJ. Nature Rev Cardio. 2021
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JAK2 CHIP is associated with risk of VTE
Zon RL et al. Blood 20204
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How to contextualize this risk?
Marnell CS et al. J Mol Cell Cardiol 2021;
Zon RL et al. Blood 2024
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Risk factor for ASCVD on par with widely established risks
Is it as modifiable?
Highest genetic risk for first VTE, but lower prevalence in general population
Should we be screening?
Hypothesized role of CH in ASCVD and interventions
Nathan DI et al. Crit Rev Oncol Hem. 2023
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CHIP increases risk for non-coronary heart disease
Schuermans A, et al., JAMA Netw Open, 2024
Saaddatagah S, et al., JAMA Cardiology, 2024
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Heart failure
Atrial Fibrillation
Murine CHIP worsens cardiomyopathy phenotype
Inoue S., et al., JACC Basic Trans Science, 2024
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CHIP is risk factor for cardiovascular diseases
Tall AR and Fuster JJ. Nature Cardiovasc. Res. 2022
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Opportunities for intervention in CH
Figure courtesy of Lilas Armstrong-Davies. Please do not share without permission.
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In the clinic: predicting risk of progression to malignancy
Weeks L et al., NEJM Evidence, 2023
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Clonal Hematopoiesis Risk Score
(CHRS)
CHRSapp.com
High CHRS associates with cardiovascular mortality
Saadatagah, S. et al. Jama Netw. Open. 2024
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Mount Sinai CH Program
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CH Program
Clinic recruitment
Prospective database
Multi-disciplinary collaboration
Individual risk assessments
Clinical trials
Downstream referrals
Acknowledgements
Bridget Marcellino, MD PhD
Ronald Hoffman, MD
John Mascarenhas, MD
Joseph Sparano, MD
Johnson Liu, MD
Keith Sigel, MD PhD
Franco Izzo, PhD
Max Dougherty, MD PhD
Nikolaus Spyrou, MD
Manasa Bhatta, MD
Eunyoung Yang, MS
Sushruta Iruvanti, MD
Ayman Mohammad
Tehilla Brander, MS CGC
Julie Gold, MS CGC
Deborah Paul, MS CGC
Zeynep Gümüş, PhD
Myvizhi Esai Selvan, PhD
Daniela Guisado, MD
Louis Cohen, MD
T32 CA225617
Jenny Lin, MD
Juan Wisnivesky, MD
Guy Montgomery, PhD
K12 CA270375
Janice Gabrilove, MD
James Ferrara, MD
Nina Bhardwaj, MD PhD
Samir Parekh, MD
Questions?
Daniel.Nathan@mssm.edu
+1 (917) 922-7010