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Clonal hematopoiesis in cardiovascular disease and therapeutic implications

Nature Cardiovascular Research volume 1, pages 116–124 (2022)Cite this article

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Abstract

Clonal hematopoiesis arises from somatic mutations that provide a fitness advantage to hematopoietic stem cells and the outgrowth of clones of blood cells. Clonal hematopoiesis commonly involves mutations in genes that are involved in epigenetic modifications, signaling and DNA damage repair. Clonal hematopoiesis has emerged as a major independent risk factor in atherosclerotic cardiovascular disease, thrombosis and heart failure. Studies in mouse models of clonal hematopoiesis have shown an increase in atherosclerosis, thrombosis and heart failure, involving increased myeloid cell inflammatory responses and inflammasome activation. Although increased inflammatory responses have emerged as a common underlying principle, some recent studies indicate mutation-specific effects. The discovery of the association of clonal hematopoiesis with cardiovascular disease and the recent demonstration of benefit of anti-inflammatory treatments in human cardiovascular disease converge to suggest that anti-inflammatory treatments should be directed to individuals with clonal hematopoiesis. Such treatments could target specific inflammasomes, common downstream mediators such as IL-1β and IL-6, or mutations linked to clonal hematopoiesis.

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Fig. 1: Somatic mutations and clonal hematopoiesis: at the crossroads of hematological malignancies and cardiovascular disease.
Fig. 2: Mutation-specific mechanisms linking clonal hematopoiesis to atherosclerotic cardiovascular disease.

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References

  1. Marnell, C. S., Bick, A. & Natarajan, P. Clonal hematopoiesis of indeterminate potential (CHIP): linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease. J. Mol. Cellular Cardiol. 161, 98–105 (2021).

    Article  CAS  Google Scholar 

  2. Steensma, D. P. et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126, 9–16 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014). These authors discovered that people with clonal hematopoiesis were at increased risk of developing both hamatological malignancies and atherosclerotic cardiovascular disease.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yu, B. et al. Supplemental association of clonal hematopoiesis with incident heart failure. J. Am. Coll. Cardiol. 78, 42–52 (2021). In a meta-analysis of different studies some, but not all, CHIP variants were found to be associated with an increased incidence of heart failure.

    Article  CAS  PubMed  Google Scholar 

  5. Pascual-Figal, D. A. et al. Clonal hematopoiesis and risk of progression of heart failure with reduced left ventricular ejection fraction. J. Am. Coll. Cardiol. 77, 1747–1759 (2021).

    Article  PubMed  Google Scholar 

  6. Dorsheimer, L. et al. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA cardiology 4, 25–33 (2019).

    Article  PubMed  Google Scholar 

  7. Mas-Peiro, S. et al. Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. Eur. Heart J. 41, 933–939 (2020).

    Article  CAS  PubMed  Google Scholar 

  8. Jaiswal, S. & Ebert, B. L. Clonal hematopoiesis in human aging and disease. Science 366, eaan4673 (2019).

  9. Jaiswal, S. & Libby, P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat. Rev. Cardiol. 17, 137–144 (2020).

    Article  PubMed  Google Scholar 

  10. Libby, P. et al. Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week. J. Am. Coll. Cardiol. 74, 567–577 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yura, Y., Sano, S. & Walsh, K. Clonal hematopoiesis: a new step linking inflammation to heart failure. JACC Basic Transl. Sci. 5, 196–207 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Heyde, A. et al. Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis. Cell 184, 1348–1361 (2021). This study provides evidence in mice and humans that atherosclerosis can promote the expansion of haematopoietic stem cells containing CH mutations suggesting reverse or bidirectional causation.

    Article  CAS  PubMed  Google Scholar 

  13. Libby, P. The changing landscape of atherosclerosis. Nature 592, 524–533 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. New Engl. J. Med. 377, 111–121 (2017).

    Article  PubMed  Google Scholar 

  15. Zekavat, S. M. et al. TP53-mediated clonal hematopoiesis confers increased risk for incident peripheral artery disease. Preprint at medRxiv https://doi.org/10.1101/2021.08.22.21262430 (2021).

  16. Young, A. L., Challen, G. A., Birmann, B. M. & Druley, T. E. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hannum, G. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Molecular cell 49, 359–367 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Levine, M. E. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging 10, 573–591 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Robertson, N. A. et al. Age-related clonal haemopoiesis is associated with increased epigenetic age. Curr. Biol. 29, R786–R787 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Nachun, D. et al. Clonal hematopoiesis associated with epigenetic aging and clinical outcomes. Aging Cell 20, e13366 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Busque, L. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44, 1179–1181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ko, M. et al. Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. PNAS 108, 14566–14571 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang, Q. et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389–393 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fuster, J. J. et al. Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017). This study demonstrated accelerated atherosclerosis in a mouse model of Tet2 deficiency CH and implicated NLRP3 inflammasome activation as a major underlying mechanism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu, D. J. et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat. Genet. 49, 1758–1766 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bick, A. G. et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 586, 763–768 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cordua, S. et al. Prevalence and phenotypes of JAK2V617F and calreticulin mutations in a Danish general population. Blood 134, 469–479 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Yokokawa, T. et al. Crucial role of hematopoietic JAK2V617F in the development of aortic aneurysms. Haematologica 106, 1910–1922 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Luque Paz, D., Ashcroft, P. & Skoda, R. C. Myeloproliferative neoplasms: the long wait for JAK2-mutant clone expansion. Cell Stem Cell 28, 359–361 (2021).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, W. et al. Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 (V617F) mice. Circ. Res. 123, e35–e47 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fidler, T. P. et al. The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis. Nature 592, 296–301 (2021). These authors implicate AIM2 inflammasome activation in the accelerated atherosclerosis of Jak2VF clonal hematopoiesis mice and show beneficial effects of treatment with IL-1β antibodies.

    Article  CAS  PubMed  Google Scholar 

  33. Edelmann, B. et al. JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation. J. Clin. Invest. 128, 4359–4371 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hu, B. et al. The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science 354, 765–768 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nilsson, J. & Hansson, G. K. The changing face of atherosclerotic plaque inflammation. J. Intern. Med. 278, 430–432 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Challen, G. A. & Goodell, M. A. Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood 136, 1590–1598 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Rauch, P. J. et al. Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and convergent macrophage phenotypes in mice. Blood 132, 745 (2018).

    Article  Google Scholar 

  39. Sano, S. et al. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease. Circ. Res. 123, 335–341 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lim, J. Y. et al. DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells. J. Exp. Med. 218, e20202733 (2021)

  41. Kim, P. G. et al. Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis. J. Exp. Med. 218, e20211872 (2021).

  42. Falanga, A. & Marchetti, M. Thrombotic disease in the myeloproliferative neoplasms. Hematology/the Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2012, 571–581 (2012).

    Google Scholar 

  43. Wolach, O. et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl. Med. 10, eaan8292 (2018).

  44. Zhao, B. et al. Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms. J. Clin. Invest. 128, 125–140 (2018).

    Article  PubMed  Google Scholar 

  45. Gudbjartsson, D. F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342–347 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Wang, W. et al. LNK/SH2B3 loss of function promotes atherosclerosis and thrombosis. Circ. Res. 119, e91–e103 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dou, H. et al. Oxidized phospholipids promote NETosis and arterial thrombosis in LNK(SH2B3) deficiency. Circulation 144, 1940–1954 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cremer, S. et al. Multiple somatic mutations for clonal hematopoiesis are associated with increased mortality in patients with chronic heart failure. Circ. Genom. Precis. Med. 13, e003003 (2020).

    Article  PubMed  Google Scholar 

  49. Palomo, L. et al. Prevalence and characteristics of clonal hematopoiesis in heart failure. Rev. Esp. Cardiol. 74, 996–999 (2021).

    Article  PubMed  Google Scholar 

  50. Assmus, B. et al. Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations. Eur. Heart J. 42, 257–265 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. Kiefer, K. C. et al. Full spectrum of clonal haematopoiesis-driver mutations in chronic heart failure and their associations with mortality. ESC Heart Fail 8, 1873–1884 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Adamo, L., Rocha-Resende, C., Prabhu, S. D. & Mann, D. L. Reappraising the role of inflammation in heart failure. Nat. Rev. Cardiol. 17, 269–285 (2020).

    Article  PubMed  Google Scholar 

  53. Abplanalp, W. T. et al. Clonal hematopoiesis-driver DNMT3A mutations alter immune cells in heart failure. Circ. Res. 128, 216–228 (2021).

    Article  CAS  PubMed  Google Scholar 

  54. Sano, S. et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. J. Am. Coll. Cardiol. 71, 875–886 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang, Y. et al. Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction. JCI Insight 5, e135204 (2020)

  56. Sano, S. et al. JAK2V617F-mediated clonal hematopoiesis accelerates pathological remodeling in murine heart failure. JACC Basic Transl. Sci. 4, 684–697 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bolton, K. L. et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat. Genet. 52, 1219–1226 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sano, S. et al. TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response. JCI Insight 6, e146076 (2021).

  59. Yura, Y. et al. The cancer therapy-related clonal hematopoiesis driver gene Ppm1d promotes inflammation and non-ischemic heart failure in mice. Circ. Res. 129, 684–698 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hormaechea-Agulla, D. et al. Chronic infection drives Dnmt3a loss-of-function clonal hematopoiesis via IFNγ signaling. Cell Stem Cell 28, 1428–1442(2021).

    Article  CAS  PubMed  Google Scholar 

  61. Cai, Z. et al. Inhibition of inflammatory signaling in Tet2 mutant preleukemic cells mitigates stress-induced abnormalities and clonal hematopoiesis. Cell Stem Cell 23, 833–849 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Avagyan, S. et al. Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis. Science 374, 768–772 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Yvan-Charvet, L. et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328, 1689–1693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Murphy, A. J. et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J. Clin. Invest. 121, 4138–4149 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Harslof, M., Pedersen, K. M., Nordestgaard, B. G. & Afzal, S. Low high-density lipoprotein cholesterol and high white blood cell counts: a mendelian randomization study. Arter. Thromb. Vasc. Biol. 41, 976–987 (2021).

    Article  CAS  Google Scholar 

  66. Adamstein, N. H. et al. The neutrophil–lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. Eur. Heart J. 42, 896–903 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bonnefond, A. et al. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat. Genet. 45, 1040–1043 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Fuster, J. J. et al. TET2-loss-of-function-driven clonal hematopoiesis exacerbates experimental insulin resistance in aging and obesity. Cell Rep. 33, 108326 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Honigberg, M. C. et al. Premature menopause, clonal hematopoiesis, and coronary artery disease in postmenopausal women. Circulation 143, 410–423 (2021).

    Article  PubMed  Google Scholar 

  70. Ruth, K. S. et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature 596, 393–397 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lusis, A. J. A vicious cycle in atherosclerosis. Cell 184, 1139–1141 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Sanchez-Cabo, F. & Fuster, J. J. Clonal haematopoiesis and atherosclerosis: a chicken or egg question? Nat. Rev. Cardiol. 18, 463–464 (2021).

    CAS  Google Scholar 

  73. Ogawa, M. Differentiation and proliferation of hematopoietic stem cells. Blood 81, 2844–2853 (1993).

    Article  CAS  PubMed  Google Scholar 

  74. Bick, A. G. et al. Genetic IL-6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis. Circulation https://doi.org/10.1161/CIRCULATIONAHA.119.044362 (2019). In people with TET2 or DNMT3A clonal hematopoiesis the increased risk of atherosclerotic CVD was reversed if they also carried a genetic variant in the IL-6 receptor that reduced its function.

  75. Heron, M. Deaths: leading causes for 2015. Natl. Vital Stat. Rep. 66, 1–76 (2017).

    PubMed  Google Scholar 

  76. Vallejo-Vaz, A. J. et al. Triglyceride-rich lipoprotein cholesterol and risk of cardiovascular events among patients receiving statin therapy in the TNT trial. Circulation 138, 770–781 (2018).

    Article  CAS  PubMed  Google Scholar 

  77. Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722 (2017).

    Article  CAS  PubMed  Google Scholar 

  79. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  80. Nidorf, S. M. et al. Colchicine in patients with chronic coronary disease. N. Engl. J. Med. 383, 1838–1847 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Tardif, J. C. et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N. Engl. J. Med. 381, 2497–2505 (2019).

    Article  CAS  PubMed  Google Scholar 

  82. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Misawa, T. et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 14, 454–460 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Imazio, M. & Nidorf, M. Colchicine and the heart. Eur. Heart J. 42, 2745–2760 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Newby, L. K. Inflammation as a treatment target after acute myocardial infarction. N.Engl. J. Med. 381, 2562–2563 (2019).

    Article  PubMed  Google Scholar 

  86. Ren, G. M. et al. Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases. Sci. Immunol. 6, eabe2933 (2021).

  87. Mangan, M. S. J. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discovery 17, 588–606 (2018).

    Article  CAS  PubMed  Google Scholar 

  88. Paulin, N. et al. Double-Strand DNA sensing Aim2 inflammasome regulates atherosclerotic plaque vulnerability. Circulation 138, 321–323 (2018).

    Article  PubMed  Google Scholar 

  89. Dinarello, C. A., Novick, D., Kim, S. & Kaplanski, G. Interleukin-18 and IL-18 binding protein. Front. Immunol. 4, 289 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Whitman, S. C., Ravisankar, P. & Daugherty, A. Interleukin-18 enhances atherosclerosis in apolipoprotein E−/− mice through release of interferon-gamma. Circ. Res. 90, E34–E38 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Wang, J. et al. Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter. Nat. Med. 21, 820–826 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gupta, S. et al. IFN-γ potentiates atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 2752–2761 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ridker, P. M. & Rane, M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular Disease. Circ. Res. 128, 1728–1746 (2021).

    Article  CAS  PubMed  Google Scholar 

  94. Galicia, J. C. et al. Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced. Genes Immun. 5, 513–516 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Huber, S. A., Sakkinen, P., Conze, D., Hardin, N. & Tracy, R. Interleukin-6 exacerbates early atherosclerosis in mice. Arter. Thromb. Vasc. Biol. 19, 2364–2367 (1999).

    Article  CAS  Google Scholar 

  96. Schuett, H. et al. Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arter. Thromb. Vasc. Biol. 32, 281–290 (2012).

    Article  CAS  Google Scholar 

  97. Schieffer, B. et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation 110, 3493–3500 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Pierini, F. S. et al. Effect of tocilizumab on LDL and HDL characteristics in patients with rheumatoid arthritis. An observational study. Rheumatol. Ther. 8, 803–815 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Ridker, P. M. et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 397, 2060–2069 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Blaschke, K. et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500, 222–226 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cimmino, L. et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170, 1079–1095(2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tang, Y. et al. Inhibition of JAK2 suppresses myelopoiesis and atherosclerosis in Apoe−/− mice. Cardiovasc. Drugs Ther. 34, 145–152 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rao, T. N. et al. JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms. Blood 134, 1832–1846 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Rocca, B. et al. A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia. Blood 136, 171–182 (2020).

    Article  PubMed  Google Scholar 

  105. Bersenev, A. et al. Lnk constrains myeloproliferative diseases in mice. J. Clin. Invest. 120, 2058–2069 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lv, K. et al. CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies. Genes Dev. 31, 1007–1023 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

A.T. and J.J.F. are supported by a grant from the Leducq Foundation (TNE-18CVD04). A.T. is supported by NIH grant 155431. We thank M. A. Zuriaga for assistance with figure design.

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  1. Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY, USA

    Alan R. Tall

  2. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    Jose J. Fuster

  3. CIBER en Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain

    Jose J. Fuster

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A.T. and J.J.F. researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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A.T. is a consultant for Amgen and CSL and is on the scientific advisory board of Staten Biotech and 1016 Biotech. J.J.F. declares no potential conflicts of interest.

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Tall, A.R., Fuster, J.J. Clonal hematopoiesis in cardiovascular disease and therapeutic implications. Nat Cardiovasc Res 1, 116–124 (2022). https://doi.org/10.1038/s44161-021-00015-3

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