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Clonal hematopoiesis, aging, and cardiovascular diseases

  • Evangelia Pardali
    Affiliations
    Department of Medicine, Hematology/Oncology, Goethe University Hospital, Frankfurt, Germany
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  • Stefanie Dimmeler
    Affiliations
    Institute for Cardiovascular Regeneration, Goethe University, Frankfurt, Germany

    Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Berlin, Germany
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  • Andreas M. Zeiher
    Affiliations
    Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Berlin, Germany

    Department of Medicine, Cardiology, Goethe University Hospital, Frankfurt, Germany
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  • Michael A. Rieger
    Correspondence
    Offprint requests to: Michael A. Rieger, PhD, Hematology/Oncology, Department of Medicine II, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
    Affiliations
    Department of Medicine, Hematology/Oncology, Goethe University Hospital, Frankfurt, Germany

    German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Frankfurt Cancer Institute, Frankfurt, Germany
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Open AccessPublished:December 29, 2019DOI:https://doi.org/10.1016/j.exphem.2019.12.006

      Highlights

      • Clonal hematopoiesis (CH) is associated with atherosclerosis, heart failure, and stroke.
      • Common risk factors prompt CH, cancer, and cardiovascular diseases (CVD).
      • Inflammation promotes CVD and affects tissue regeneration.
      • The outcome of heart failure and aortic valve stenosis patients with DNMT3A/TET2-CH mutations is poor.
      • A vicious circuit is induced by CH-mutated myeloid cells on CVDs and hematopoiesis.
      Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Many studies have provided evidence that both genetic and environmental factors induce atherosclerosis, leading thus to cardiovascular complications. Atherosclerosis is an inflammatory disease, and aging is strongly associated with the development of atherosclerosis. Recent experimental evidence suggests that clonal hematopoiesis (CH) is an emerging cardiovascular risk factor that contributes to the development of atherosclerosis and cardiac dysfunction and exacerbates cardiovascular diseases. CH is caused by somatic mutations in recurrent genes in hematopoietic stem cells, leading to the clonal expansion of mutated blood cell clones. Many of the mutated genes are known in the context of myeloid neoplasms. However, only some individuals carrying CH mutations develop hematologic abnormalities. CH is clearly age dependent and is not rare: at least 10%–20% of people >70 years old carry CH. The newly discovered association between myeloid leukemia-driver mutations and the progression of CVDs has raised medical interest. In this review, we summarize the current view on the contribution of CH in different cardiovascular diseases, CVD risk assessment, patient stratification, and the development of novel therapeutic strategies.
      Despite advances in the medical and interventional clinical management of patients, cardiovascular diseases (CVDs) remain the leading cause of death worldwide. It is well appreciated that atherosclerosis represents the underlying cause of most CVDs [
      • Libby P.
      History of discovery: inflammation in atherosclerosis.
      ]. Atherosclerosis is a chronic inflammatory disease that leads to the formation of atheromatous lesions in the vessel associated with increased recruitment, adhesion, and proliferation of different leukocyte subsets to the endothelium [
      • Libby P.
      History of discovery: inflammation in atherosclerosis.
      ]. Several cardiovascular risk factors (CRFs) have been found to enhance the risk of CVD (Figure 1), including hypercholesterolemia (HC), diabetes mellitus (DM), hypertension, metabolic syndrome, obesity, and smoking [
      • Pardali E
      • Waltenberger J.
      Monocyte function and trafficking in cardiovascular disease.
      ]. Inflammation plays a crucial role in the development of CVDs and several studies have reported that CRFs enhance production of myeloid cells and multipotent hematopoietic progenitors in the bone marrow and in this way may promote atherosclerosis and disease development [
      • Dragoljevic D
      • Westerterp M
      • Veiga CB
      • Nagareddy P
      • Murphy AJ
      Disordered haematopoiesis and cardiovascular disease: a focus on myelopoiesis.
      ].
      Figure 1
      Figure 1Commonalities of clonal hematopoiesis, myeloid neoplasms, and cardiovascular diseases. Many shared risk factors suggest a causal relation between the origin and progression of blood-related alterations and cardiovascular diseases.
      Increasing evidence suggests that conventional CRFs are not fully predictive of the development of CVDs and, more importantly, that the incidence of CVDs increases with age [
      • North BJ
      • Sinclair DA.
      The intersection between aging and cardiovascular disease.
      ,
      • Fajemiroye JO
      • da Cunha LC
      • Saavedra-Rodríguez R
      • et al.
      Aging-induced biological changes and cardiovascular diseases.
      ]. Although the effect of aging on the development of atherosclerosis has been considered to be caused by cumulative exposure to classic CRFs, the exact molecular mechanisms of age predisposition to CVDs are not completely understood. Several studies have linked cardiovascular aging to genomic instability, telomere attrition, and accumulating irreversible epigenetic alterations, including DNA methylation, histone posttranslational modifications, and dynamic nucleosome occupancy [
      • Zhang W
      • Song M
      • Qu J
      • Liu GH
      Epigenetic modifications in cardiovascular aging and diseases.
      ,
      • Zarzour A
      • Kim HW
      • Weintraub NL
      Epigenetic regulation of vascular diseases.
      ,
      • Gallagher KA
      • Joshi A
      • Carson WF
      • et al.
      Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes.
      ].
      Recent elegant studies have provided evidence that clonal hematopoiesis (CH) is a novel causal CRF for CVDs in elderly individuals, as previously reviewed [
      • Sano S
      • Wang Y
      • Walsh K
      Clonal hematopoiesis and its impact on cardiovascular disease.
      ,
      • Libby P
      • Sidlow R
      • Lin AE
      • et al.
      Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week.
      ]. CH was initially described in elderly people who develop hematologic malignancies. CH originates from somatic mutations in hematopoietic stem cells (HSCs) in genes implicated in myeloid neoplasms and results in expansion of mutated blood cell clones. Clonal hematopoiesis of indeterminate potential (CHIP) is technically defined by the presence of somatic variants with a variant allele frequency (VAF) (i.e., variant prevalence among all blood cells) of at least 2%, but without the presence of hematologic malignancies or other hematologic abnormalities [
      • Steensma DP
      • Bejar R
      • Jaiswal S
      • et al.
      Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.
      ]. Genetic and epidemiology studies in humans revealed that CHIP correlated with increased mortality in individuals with CVDs. Preclinical animal models provided mechanistic evidence for the role of CHIP in the progression and development of CVD. In this review, we summarize the role of inflammation and inflammatory blood cell types in the development of atherosclerosis and CVDs. We also discuss the potential mechanisms by which CH contributes to increased cardiovascular risk in aging individuals and how increased inflammation, induced by cardiovascular risk factors, further promotes the clonal dominance of mutated HSC clones, leading to a feedback loop between CH and CVDs. Finally, we raise potential implications of these findings in CVD risk assessment, patient stratification, and the development of novel therapeutic strategies.

      Role of myeloid cells and inflammation in the development of CVD

      Atherosclerosis is a chronic inflammatory disease of the vasculature. It is well appreciated that monocyte-derived macrophages play a crucial role in the progression of atherosclerosis, plaque development, and the incidence of CVD [
      • Libby P.
      History of discovery: inflammation in atherosclerosis.
      ,
      • Pardali E
      • Waltenberger J.
      Monocyte function and trafficking in cardiovascular disease.
      ]. Pathological stimuli such as hyperlipidemia and hypertension increase monocyte adhesion on the endothelium and their infiltration into the vessel wall during atherogenesis [
      • Libby P.
      History of discovery: inflammation in atherosclerosis.
      ,
      • Pardali E
      • Waltenberger J.
      Monocyte function and trafficking in cardiovascular disease.
      ]. After entering the vessel wall, monocytes start to proliferate and differentiate into macrophages, which endocytose lipids and develop into foam cells, which contribute to plaque development [
      • Libby P.
      History of discovery: inflammation in atherosclerosis.
      ,
      • Pardali E
      • Waltenberger J.
      Monocyte function and trafficking in cardiovascular disease.
      ]. It has been reported that increased numbers of circulating monocytes (monocytosis) correlate with plaque formation and the development of carotid artery disease (CAD) [
      • Libby P.
      History of discovery: inflammation in atherosclerosis.
      ,
      • Olivares R
      • Ducimetière P
      • Claude JR
      Monocyte count: a risk factor for coronary heart disease?.
      ,
      • Johnsen SH
      • et al.
      Monocyte count is a predictor of novel plaque formation: a 7-year follow-up study of 2610 persons without carotid plaque at baseline the Tromsø Study.
      ]. Experimental evidence has established a causal relationship between monocytosis and the development of atherosclerosis in preclinical models [
      • Libby P.
      History of discovery: inflammation in atherosclerosis.
      ,
      • Pardali E
      • Waltenberger J.
      Monocyte function and trafficking in cardiovascular disease.
      ]. Monocyte depletion or inhibition of monocyte recruitment results in reduced atherogenesis and plaque formation in experimental models of atherosclerosis [
      • Ylitalo R
      • Oksala O
      • Ylä-Herttuala S
      • Ylitalo P
      Effects of clodronate (dichloromethylene bisphosphonate) on the development of experimental atherosclerosis in rabbits.
      ,
      • Stoneman V
      • et al.
      Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques.
      ,
      • Rajavashisth T
      • Qiao JH
      • Tripathi S
      • et al.
      Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor-deficient mice.
      ,
      • Bannon P
      • Wood S
      • Restivo T
      • Campbell L
      • Hardman MJ
      • Mace KA
      Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice.
      ,
      • Potteaux S
      • Gautier EL
      • Hutchison SB
      • et al.
      Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe–/– mice during disease regression.
      ]. Several CRFs have been found to increase the risk of CVDs by inducing myelopoiesis and hematopoiesis (Figure 1). Hypercholesterolemia, diabetes, and obesity increase the number of circulating monocytes, resulting thus in acceleration of atherosclerosis [
      • Nagareddy PR
      • Murphy AJ
      • Stirzaker RA
      • et al.
      Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.
      ,
      • Nagareddy PR
      • Kraakman M
      • Masters SL
      • et al.
      Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity.
      ,
      • Swirski FK
      • Libby P
      • Aikawa E
      • et al.
      Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata.
      ]. Moreover, hypercholesterolemia promotes hematopoietic stem and progenitor cell (HSPC) proliferation and, in this way, contributes to increased myelopoiesis and exacerbated atherosclerosis [
      • Murphy AJ
      • Dragoljevic D
      • Tall AR
      Cholesterol efflux pathways regulate myelopoiesis: a potential link to altered macrophage function in atherosclerosis.
      ,
      • Murphy AJ
      • Akhtari M
      • Tolani S
      • et al.
      ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice.
      ,
      • Tall AR
      • Yvan-Charvet L.
      Cholesterol, inflammation and innate immunity.
      ,
      • Tolani S
      • Pagler TA
      • Murphy AJ
      • et al.
      Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: studies in mice and FH children.
      ,
      • Dragoljevic D
      • Kraakman MJ
      • Nagareddy PR
      • et al.
      Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis.
      ]. Similarly, other studies have found that diabetes and hyperglycemia influence HSC function, differentiation, and mobilization and in this way further contribute to the development of CVDs [
      • Ferraro F
      • Lymperi S
      • Méndez-Ferrer S
      • et al.
      Diabetes impairs hematopoietic stem cell mobilization through alteration of niche function.
      ,
      • Hazra S
      • Jarajapu YPR
      • Stepps V
      • et al.
      Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model.
      ,
      • Orlandi A
      • Chavakis E
      • Seeger F
      • Tjwa M
      • Zeiher AM
      • Dimmeler S
      Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice.
      ]. Diabetes results in reduced numbers of HSCs and interferes with their repopulation capacity in a competitive engraftment experiment and their cytokine expression patterns [
      • Orlandi A
      • Chavakis E
      • Seeger F
      • Tjwa M
      • Zeiher AM
      • Dimmeler S
      Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice.
      ]. Furthermore, diabetes leads to increased expression of plasma levels of the alarmins S100A8 and S100A9 secreted by neutrophils, resulting in increased proliferation of granulocyte–monocyte progenitors (GMPs) and enhanced myelopoiesis [
      • Nagareddy PR
      • Murphy AJ
      • Stirzaker RA
      • et al.
      Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.
      ,
      • Nagareddy PR
      • Kraakman M
      • Masters SL
      • et al.
      Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity.
      ].

      Somatic mutations in hematopoietic stem cells drive clonal hematopoiesis

      Clearly, aging poses the largest risk for the development of CVDs; this is due not only to the accumulative effect of the CRFs and the increased inflammatory responses but also to the accumulation of epigenetic alterations and genetic mutations. It was recently reported that CHIP contributes to the development of cardiovascular diseases in elderly individuals [
      • Jaiswal S
      • Natarajan P
      • Ebert BL
      Clonal hematopoiesis and atherosclerosis.
      ,
      • Jaiswal S
      • Fontanillas P
      • Flannick J
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ,
      • Genovese G
      • Kahler AK
      • Handsaker RE
      • et al.
      Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
      ]. Before discussing the role of CHIP in the development of CVD, it is important to review the basis of CH.
      Hematological malignancies ensue from the clonal expansion of transformed blood cells, and are generally diseases of the elderly, as the median age for most of these diseases is between 60 and 70 years. Although, in certain cases, they can be associated with inherited genetic mutations, hematologic malignancies usually originate from recurrent somatic mutations in driver genes [
      • Welch JS
      • Ley TJ
      • Link DC
      • et al.
      The origin and evolution of mutations in acute myeloid leukemia.
      ,
      • Bowman RL
      • Busque L
      • Levine RL
      Clonal hematopoiesis and evolution to hematopoietic malignancies.
      ]. Interestingly, although most of the somatic mutations have no effect, certain mutations result in increased proliferation or, alternatively, reduced cell death and enhanced self-renewal and, as a result, confer a specific clonal expansion advantage to the HSCs carrying these mutations [
      • Beerman I
      • Bhattacharya D
      • Zandi S
      • et al.
      Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion.
      ]; this may lead to hematologic malignancies. Clonality was also found to be a major characteristic of the aging hematopoietic system. Studies in women over the age of 65, with no hematologic malignancies, suggested that there is a skewed pattern of X-chromosome inactivation in peripheral blood cells, particularly within the myeloid compartment, which is age related [
      • Busque L
      • Mio R
      • Mattioli J
      • et al.
      Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age.
      ,
      • Fey MF
      • Liechti-Gallati S
      • von Rohr A
      • et al.
      Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe.
      ,
      • Gale RE
      • Fielding AK
      • Harrison CN
      • Linch DC
      Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age.
      ]. Subsequently, Busque and colleagues demonstrated by exome sequencing the presence of somatic, recurrent TET2 mutations in normal elderly individuals with clonal hematopoiesis but without hematological malignancies [
      • Busque L
      • Patel JP
      • Figueroa M
      • et al.
      Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis.
      ]. TET2 mutations were previously reported to be associated with myeloid cancers [
      • Delhommeau F
      • Dupont S
      • Della Valle V
      • et al.
      Mutation in TET2 in myeloid cancers.
      ].
      Subsequent studies using whole-exome sequencing as well as gene-targeted sequencing assisted the detection of several somatic mutations with low VAF [
      • Jaiswal S
      • Fontanillas P
      • Flannick J
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ,
      • Genovese G
      • Kahler AK
      • Handsaker RE
      • et al.
      Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
      ]. These studies provided evidence that the majority of the age-associated recurrent mutations were in genes such as DNMT3A, TET2, JAK2, TP53, ASXL1, SF3B1, PPM1D, and BCORL1, known to be associated with acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), or myelodysplastic syndrome (MDS) [
      • Xie M
      • Lu C
      • Wang J
      • et al.
      Age-related cancer mutations associated with clonal hematopoietic expansion.
      ]. Interestingly, other mutations in genes found to play an important role in AML development and progression, such as FLT3, IDH1, IDH2, and NPM1, were not so common in CH [
      • Jaiswal S
      • Natarajan P
      • Ebert BL
      Clonal hematopoiesis and atherosclerosis.
      ,
      • Jaiswal S
      • Fontanillas P
      • Flannick J
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ,
      • Xie M
      • Lu C
      • Wang J
      • et al.
      Age-related cancer mutations associated with clonal hematopoietic expansion.
      ,
      • Coombs CC
      • Zehir A
      • Devlin SM
      • et al.
      Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome.
      ,
      • Papaemmanuil E
      • Gerstung M
      • Bullinger L
      • et al.
      Genomic classification and prognosis in acute myeloid leukemia.
      ]. All identified mutations increased with age. Subsequent complementary studies of large cohorts of patients utilizing sensitive error-corrected, targeted deep sequencing [
      • Abelson S
      • Collord G
      • Ng SWK
      • et al.
      Prediction of acute myeloid leukaemia risk in healthy individuals.
      ,
      • Young AL
      • Challen GA
      • Birmann BM
      • Druley TE
      Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.
      ] further supported these results, indicating that recurrent mutations in genes associated with leukemia are increased in aged individuals and correlated with clonal hematopoiesis [
      • Jaiswal S
      • Natarajan P
      • Ebert BL
      Clonal hematopoiesis and atherosclerosis.
      ,
      • Jaiswal S
      • Fontanillas P
      • Flannick J
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ,
      • Genovese G
      • Kahler AK
      • Handsaker RE
      • et al.
      Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
      ,
      • Young AL
      • Challen GA
      • Birmann BM
      • Druley TE
      Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.
      ,
      • Shlush LI
      • Zandi S
      • Mitchell A
      • et al.
      Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.
      ,
      • McKerrell T
      • Park N
      • Moreno T
      • et al.
      Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis.
      ], but without leading to hematological malignancies. This type of CH was technically defined as CHIP and is characterized by the presence of recurrent mutations with a VAF of at least 2% in aged individuals in the absence of hematologic cancer or other clonal disease [
      • Steensma DP
      • Bejar R
      • Jaiswal S
      • et al.
      Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.
      ]. Although the frequency of CHIP is less than 1% in individuals younger than 40 years, its prevalence increases to 15%–20% in people older than 70 years [
      • Jaiswal S
      • Fontanillas P
      • Flannick J
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ,
      • Genovese G
      • Kahler AK
      • Handsaker RE
      • et al.
      Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
      ,
      • Xie M
      • Lu C
      • Wang J
      • et al.
      Age-related cancer mutations associated with clonal hematopoietic expansion.
      ,
      • Coombs CC
      • Zehir A
      • Devlin SM
      • et al.
      Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome.
      ]. However, the prevalence of CH is highly dependent on the sensitivity of the detection method used. Although the initial studies used whole-exome sequencing, which is relatively insensitive to smaller clones, recent studies using more sensitive, error-corrected, deep sequencing approaches have found a much higher prevalence of CH with low VAF, even at younger age. The biological and medical importance of the smaller clones still remains unclear [
      • Abelson S
      • Collord G
      • Ng SWK
      • et al.
      Prediction of acute myeloid leukaemia risk in healthy individuals.
      ,
      • Acuna-Hidalgo R
      • Sengul H
      • Steehouwer M
      • et al.
      Ultra-sensitive sequencing identifies high prevalence of clonal hematopoiesis-associated mutations throughout adult life.
      ].

      Association of clonal hematopoiesis with CVDs

      Although CH was initially associated with hematologic malignancies, it became evident that CH led to decreased patient survival, which could not be explained by the increase in hematological cancer [
      • Jaiswal S
      • Natarajan P
      • Ebert BL
      Clonal hematopoiesis and atherosclerosis.
      ,
      • Jaiswal S
      • Fontanillas P
      • Flannick J
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ,
      • Genovese G
      • Kahler AK
      • Handsaker RE
      • et al.
      Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
      ,
      • Coombs CC
      • Zehir A
      • Devlin SM
      • et al.
      Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome.
      ] Different studies using next-generation sequencing analysis in large cohorts revealed that CHIP-driver mutations in leukemia-related genes DNMT3A, TET2, ASXL1, and JAK2 were associated with an increased risk of incidence of coronary heart disease (CHD) or stroke and increased mortality [
      • Jaiswal S
      • Natarajan P
      • Ebert BL
      Clonal hematopoiesis and atherosclerosis.
      ,
      • Jaiswal S
      • Fontanillas P
      • Flannick J
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ]. Importantly it was reported that the prevalence of CHIP was higher in individuals with early onset of myocardial infarction [
      • Jaiswal S
      • Natarajan P
      • Ebert BL
      Clonal hematopoiesis and atherosclerosis.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ]. In a recent study, CHIP was also associated with chronic heart failure (CHF) caused by ischemic heart disease. It was found that the occurrence of CHIP was increased in CHF patients compared with published control cohorts, with a higher prevalence in aged patients with CHF. CHIP-driver mutations in DNMT3A or TET2 were the most prevalent causes of CHIP, representing more than 60% of CHIP carriers with CHF. CHF patients with or without CHIP did not have any difference in other clinical parameters or common classifications of CHF. Most importantly, DNMT3A or TET2 CHIP-driver mutations were associated with a poor outcome in these CHF patients, who had reduced survival and increased progression of their disease [
      • Dorsheimer L
      • Assmus B
      • Rasper T
      • et al.
      Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure.
      ]. The dosage dependence of DNMT3A- or TET2-mutated cells on the outcome in these patients suggests a causative role of mutated blood cells and the progression of CHF. The presence of DNMT3A or TET2 CHIP-driver mutations remained a significant new risk factor for CHF after multivariate correction of confounding factors. Interestingly, individuals with CHIP had increased coronary artery calcium scores, indicative of vascular wall inflammation and development of atherosclerosis [
      • Jaiswal S
      • Natarajan P
      • Ebert BL
      Clonal hematopoiesis and atherosclerosis.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ]. In line with these results, a recent study reported that CHIP is also associated with degenerative aortic valve stenosis and that mutations in DNMT3A or TET2 result in worse prognosis and increased mortality in patients undergoing transcatheter aortic valve implantation [
      • Mas-Peiro S
      • Hoffmann J
      • Fichtlscherer S
      • et al.
      Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation.
      ]. Moreover CHIP mutations in one of the driver genes, JAK2, have been associated with an increased risk of thrombosis, which correlated with increased numbers of leukocytes and acute coronary events [
      • Carobbio A
      • Finazzi G
      • Guerini V
      Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status.
      ,
      • Marchioli R
      • Finazzi G
      • Marfisi RM
      • Tognoni G
      • Barbui T
      Clinical trials in myeloproliferative disorders: looking forward.
      ,
      • Wolach O
      • Sellar RS
      • Marinod K
      • et al.
      Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms.
      ]. Hence, CHIP is now considered an additional CRF that contributes to age-related CVD development and progression (Figure 2).
      Figure 2
      Figure 2Clonal hematopoiesis is a potent cardiovascular risk factor for cardiovascular diseases. Mutations in myeloid leukemia-associated driver genes in HSCs confer an advantage in the mutated blood cell clones, leading to clonal hematopoiesis. Mutations in distinct genes are associated with increased risk and progression of atherosclerosis, heart failure, aortic stenosis, and thrombosis.

      Role of CHIP-driver gene mutations in the development of atherosclerosis and CVDs

      After establishment of a link between CHIP and CVD, several studies focused on the characterization of the fundamental mechanisms that may explain the functional association of CHIP with the development of CVD. Studies in humans and mice provided functional evidence for a differential role of distinct mutations in various CHIP-driver genes in CAD (Figure 2).
      In this respect, TET2 (ten-eleven translocation-2) is the most well-characterized gene. TET2 is a methylcytosine dioxygenase that modulates DNA hydroxymethylation by converting 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) to promote DNA demethylation [
      • Ko M
      • Huang Y
      • Jankowska AM
      • et al.
      Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.
      ]. TET2 is involved in DNA methylation and, in this way, regulates transcriptional activation or repression of many genes [
      • Ko M
      • Huang Y
      • Jankowska AM
      • et al.
      Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.
      ,
      • Ko M
      • Bandukwala HS
      • An J
      • et al.
      Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice.
      ]. TET2 loss of function leads to dysregulated expansion of HSCs, enhanced repopulating capacity of HSCs in vivo, and an altered cell differentiation skewing toward monocytic/granulocytic lineages [
      • Delhommeau F
      • Dupont S
      • Della Valle V
      • et al.
      Mutation in TET2 in myeloid cancers.
      ,
      • Ko M
      • Bandukwala HS
      • An J
      • et al.
      Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice.
      ,
      • Li Z
      • Cai X
      • Cai CL
      • et al.
      Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies.
      ,
      • Langemeijer SM
      • Kuiper RP
      • Berends M
      • et al.
      Acquired mutations in TET2 are common in myelodysplastic syndromes.
      ]. TET2 mutations have been associated with increased cardiovascular risk, and it was reported that in individuals carrying TET2 mutations, levels of circulating interleukin (IL)-8 were increased twofold compared with levels in those without mutations [
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ]. In addition, patients with severe aortic valve stenosis carrying TET2 mutations had increased numbers of nonclassic inflammatory monocytes, which secrete pro-inflammatory cytokines and in this way may contribute to development of CVD [
      • Dorsheimer L
      • Assmus B
      • Rasper T
      • et al.
      Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure.
      ,
      • Mas-Peiro S
      • Hoffmann J
      • Fichtlscherer S
      • et al.
      Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation.
      ]. TET2 CH-driver mutations lead to increased bone marrow (BM) leukocytes and increased HSPC numbers in patients with CHF following ischemia, while patients carrying DNMT3A CHIP-driver mutations do not exhibit any alteration in bone marrow blood cell lineage distribution and HSPCs [
      • Dorsheimer L
      • Assmus B
      • Rasper T
      • et al.
      Hematopoietic alterations in chronic heart failure patients by somatic mutations leading to clonal hematopoiesis: CHIP-related hematopoietic alterations in CHF patients.
      ]. Studies in preclinical models revealed that atheroprone mice transplanted with TET2-deficient BM cells exhibited robust expansion in vivo and increased macrophage infiltration and atherosclerotic plaque size [
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ,
      • Fuster JJ
      • MacLauchlan S
      • Zuriaga MA
      • et al.
      Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
      ]. Further characterization revealed that TET2 deficiency results in increased expression of different chemokines such as Cxcl1, Cxcl2, and Cxcl3, as well as IL-6 and IL-1β [
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ,
      • Fuster JJ
      • MacLauchlan S
      • Zuriaga MA
      • et al.
      Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
      ,
      • Zhang Q
      • Zhao K
      • Shen Q
      • et al.
      Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6.
      ]. Increased expression of IL-1β from TET2-deficient macrophages was found to be mediated by NLRP3 inflammasome, and treatment of atherosclerosis-prone mice, transplanted with TET2-deficient BM cells, with an NLRP3 inhibitor reduced the proatherogenic effect of TET2 deficiency [
      • Fuster JJ
      • MacLauchlan S
      • Zuriaga MA
      • et al.
      Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
      ]. TET2 deficiency in HSCs increased cardiac dysfunction and fibrosis in hearts subjected to left anterior descending artery ligation or pressure overload [
      • Sano S
      • Oshima K
      • Wang Y
      • et al.
      Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome.
      ]. This was shown to be caused by increased IL-1β expression, and treatment with an NLRP3 inhibitor reversed the effects of TET2 deficiency on cardiac dysfunction [
      • Sano S
      • Oshima K
      • Wang Y
      • et al.
      Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome.
      ]. In another study, CRISPR-mediated editing of TET2 introducing inactivating mutations into mouse HSCs increased cardiac dysfunction and fibrosis in mice with angiotensin II-induced heart failure by inducing the expression of IL-1β, IL-6, and Ccl5 [
      • 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.
      ]. Although TET2 mutations result in a myeloid-bias lineage differentiation, recent studies have found that specific deletion of TET2 in regulatory T cells in mice unleashed their effector function and skewed their phenotype toward Tfh/Th17, resulting in the development of dominant inflammatory disease, suggesting that TET2 inactivation may also affect the function of other immune cells involved in the development of CVDs [
      • Yue X
      • Lio CWJ
      • Samaniego-Castruita D
      • Li X
      • Rao A
      Loss of TET2 and TET3 in regulatory T cells unleashes effector function.
      ].
      Other studies focused on the effect of DNMT3A deficiency on CVDs. DNMT3A is a DNA methyltransferase mediating DNA methylation and regulating gene expression. Interestingly, DNMT3A is the most prevalent driver gene associated with CH [
      • Jaiswal S
      • Fontanillas P
      • Flannick J
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ,
      • Genovese G
      • Kahler AK
      • Handsaker RE
      • et al.
      Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
      ]. Nevertheless, DNMT3A-deficient BM cells do not exhibit selective expansion in vivo [
      • 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.
      ,
      • Buscarlet M
      • Provost S
      • Zada YF
      • et al.
      Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A.
      ] and mainly expand in vivo after sequential BM transplantations in aged mice [
      • Zhang X
      • Su J
      • Jeong M
      • et al.
      DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells.
      ,
      • Cole CB
      • Russler-Germain DA
      • Ketkar S
      • et al.
      Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies.
      ,
      • Challen GA
      • Sun D
      • Jeong M
      • et al.
      Dnmt3a is essential for hematopoietic stem cell differentiation.
      ]. CRISPR-mediated mutagenesis of DNMT3A in mouse HSCs resulted in increased cardiac dysfunction and fibrosis in mice following angiotensin II-induced heart failure by promoting the expression of Cxcl1, Cxcl2, IL-6, and Ccl5 but not Il-1β [
      • 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.
      ]. DNMT3A deficiency may also promote a pro-atherogenic phenotype in different immune cells such as activation of mast cells and increased interferon-γ production by T cells [
      • Gamper CJ
      • Agoston AT
      • Nelson WG
      • Powell JD
      Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation.
      ,
      • Leoni C
      • Montagner S
      • Rinaldi A
      • et al.
      Dnmt3a restrains mast cell inflammatory responses.
      ,
      • Li X
      • Zhang Q
      • Ding Y
      • et al.
      Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity.
      ,
      • Pham D
      • Walline CC
      • Hollister K
      • et al.
      The transcription factor Twist1 limits T helper 17 and T follicular helper cell development by repressing the gene encoding the interleukin-6 receptor α chain.
      ,
      • Yu Q
      • Zhou B
      • Zhang Y
      • et al.
      DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation.
      ]. Moreover, it was recently reported that patients with aortic valve stenosis carrying DNTM3A recurrent mutations exhibited an increased Th17/Treg ratio, suggesting that DNMT3A mutations might promote T-cell polarization toward a pro-inflammatory phenotype that can contribute to atherosclerosis development and CVDs [
      • Mas-Peiro S
      • Hoffmann J
      • Fichtlscherer S
      • et al.
      Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation.
      ,
      • Ma Y
      • Yuan X
      • Deng L
      • et al.
      Imbalanced frequencies of Th17 and Treg cells in acute coronary syndromes are mediated by IL-6-STAT3 signaling.
      ]. The exact role of DNMT3A deficiency in atherosclerosis development remains to be further investigated.
      JAK2 (Janus kinase 2) is a signaling tyrosine kinase that associates with the signaling cascades of a variety of cytokine receptors; it has been associated with cell growth and division and is especially important for controlling blood cell production in the BM [
      • Park SO
      • Wamsley HL
      • Bae K
      • et al.
      Conditional deletion of Jak2 reveals an essential role in hematopoiesis throughout mouse ontogeny: implications for Jak2 inhibition in humans.
      ]. In addition, several studies have implicated JAK2 in the development of atherosclerosis [
      • Kirabo A
      • Embury J
      • Kiss R
      • et al.
      The stilbenoid tyrosine kinase inhibitor, G6, suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo.
      ,
      • Sivasubramaniyam T
      • Schroer SA
      • Li A
      • et al.
      Hepatic JAK2 protects against atherosclerosis through circulating IGF-1.
      ]. JAK2 is one of the genes frequently mutated in individuals with CHIP [
      • Jaiswal S
      • Fontanillas P
      • Flannick J
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ,
      • Jaiswal S
      • Natarajan P
      • Silver AJ
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ,
      • Genovese G
      • Kahler AK
      • Handsaker RE
      • et al.
      Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
      ] and leads to proliferation of HSCs. Early studies provided evidence suggesting that patients carrying the JAK2 V617F gain-of-function have a higher risk of thrombosis [
      • Xavier SG
      • Gadelha T
      • Rezende SM
      • Zalcberg IR
      • Spector N
      JAK2V617F mutation in patients with thrombosis.
      ]. Interestingly, studies in mice suggested that JAK2 V617F drives CH toward the myeloid and granulocytic lineage and enhances the pro-inflammatory activities of macrophages and neutrophils, providing a potential mechanism by which JAK2 V617F affects cardiovascular function [
      • Lundberg P
      • Takizawa H
      • Kubocakova L
      • et al.
      Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F.
      ,
      • Okugawa S
      • Ota Y
      • Kitazawa T
      • et al.
      Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages.
      ,
      • Oku S
      • Takenaka K
      • Kuriyama T
      • et al.
      JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation.
      ]. Moreover, it was reported that hematopoietic JAK2 V617F in atheroprone mice leads to acceleration of atherosclerosis and plaque instability [
      • Wang W
      • Liu W
      • Fidler T
      • et al.
      Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 V617F mice.
      ].
      Further studies are awaited that shed light on the functional role of somatic mutations in other CH-driver genes, such as TP53, ASXL1, SF3B1, PPM1D, and BCORL1, in the development of CVDs.

      Association between cancer and CVDs and the possible role of CH therein

      There is substantial biological evidence that cancer and CVD share biological mechanisms underlying their pathogenesis [
      • de Boer RA
      • Meijers WC
      • van der Meer P
      • van Veldhuisen DJ
      Cancer and heart disease: associations and relations.
      ,
      • Totzeck M
      • Schuler M
      • Stuschke M
      • Heusch G
      • Rassaf T
      Cardio-oncology—strategies for management of cancer-therapy related cardiovascular disease.
      ]. Numerous studies have proposed that there are similar risk factors for cancer (solid and hematological) and CVDs (Figure 1). The incidence of both cancer and CVDs increases with advancing age [
      • de Boer RA
      • Meijers WC
      • van der Meer P
      • van Veldhuisen DJ
      Cancer and heart disease: associations and relations.
      ,
      • Totzeck M
      • Schuler M
      • Stuschke M
      • Heusch G
      • Rassaf T
      Cardio-oncology—strategies for management of cancer-therapy related cardiovascular disease.
      ,
      • Koene RJ
      • Prizment AE
      • Blaes A
      • Konety SH
      Shared risk factors in cardiovascular disease and cancer.
      ]. Chronic inflammation plays a major role in the development of CVDs [
      • Libby P.
      History of discovery: inflammation in atherosclerosis.
      ], and now it is well appreciated that inflammation in the tumor microenvironment can promote malignant transformation and cancer progression [
      • Kuper H
      • Adami HO
      • Trichopoulos D
      Infections as a major preventable cause of human cancer.
      ,
      • Greten FR
      • Grivennikov SI.
      Inflammation and cancer: triggers, mechanisms, and consequences.
      ,
      • Crusz SM
      • Balkwill FR
      Inflammation and cancer: advances and new agents.
      ]. Interestingly, a number of CRFs such as diabetes, obesity, and smoking have been also reported to increase the prevalence of cancer [
      • Vincent L
      • Leedy D
      • Masri SC
      • Cheng RK
      Cardiovascular disease and cancer: is there increasing overlap?.
      ]. Although advances in medical care have improved longevity, they have increased the overlap between cancer and CVDs; cancer patients are at high risk of developing CVDs, and patients with CVDs or heart failure have a higher rate of cancer than healthy control subjects [
      • de Boer RA
      • Meijers WC
      • van der Meer P
      • van Veldhuisen DJ
      Cancer and heart disease: associations and relations.
      ,
      • Totzeck M
      • Schuler M
      • Stuschke M
      • Heusch G
      • Rassaf T
      Cardio-oncology—strategies for management of cancer-therapy related cardiovascular disease.
      ,
      • Koene RJ
      • Prizment AE
      • Blaes A
      • Konety SH
      Shared risk factors in cardiovascular disease and cancer.
      ,
      • Meijers WC
      • de Boer RA
      Common risk factors for heart failure and cancer.
      ]. It was found that patients with myelodysplastic syndrome, leukemia, and Hodgkin's lymphoma have an increased risk of cardiovascular complications [
      • Brunner AM
      • Blonquist TM
      • Hobbs GS
      • et al.
      Risk and timing of cardiovascular death among patients with myelodysplastic syndromes.
      ,
      • van Leeuwen FE
      • Ng AK
      Long-term risk of second malignancy and cardiovascular disease after Hodgkin lymphoma treatment.
      ,
      • van Haelst PL
      • Schot B
      • Hoendermis ES
      • van den Berg MP
      Acute myeloid leukaemia as a cause of acute ischaemic heart disease.
      ]. Moreover, arterial thrombosis is preceding cancer diagnosis in older patients [
      • Navi BB
      • Reiner AS
      • Kamel H
      • et al.
      Risk of arterial thromboembolism in patients with cancer.
      ,
      • Navi BB
      • Reiner AS
      • Kamel H
      • et al.
      Arterial thromboembolic events preceding the diagnosis of cancer in older persons.
      ], and vascular calcifications, CAD, and other cardiovascular complications are prevalent in patients with colorectal cancer [
      • Wang SC
      • Schulman-Marcus J
      • Fantauzzi J
      • et al.
      Colon cancer laterality is associated with atherosclerosis and coronary artery disease.
      ]. There is a causal relationship between heart failure/myocardial infarction (MI) and development of cancer. Analysis of the distributions of different cancer sites among patients with MI revealed that the most frequent types of cancers were colorectal cancer (22%), prostate cancer (22%), and lung cancer (16%) [
      • Rinde LB
      • Småbrekke B
      • Hald EM
      • et al.
      Myocardial infarction and future risk of cancer in the general population—the Tromsø Study.
      ]. Furthermore, the induction of MI in APCmin mice, which are prone to developing precancerous intestinal tumors, resulted in increased tumor formation and accelerated tumor growth [
      • de Boer RA
      • Meijers WC
      • van der Meer P
      • van Veldhuisen DJ
      Cancer and heart disease: associations and relations.
      ,
      • Meijers WC
      • de Boer RA
      Common risk factors for heart failure and cancer.
      ].
      CH has been also associated with nonhematological cancers [
      • Xie M
      • Lu C
      • Wang J
      • et al.
      Age-related cancer mutations associated with clonal hematopoietic expansion.
      ,
      • Coombs CC
      • Zehir A
      • Devlin SM
      • et al.
      Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome.
      ,
      • Bolton KL
      • Gillis NK
      • Coombs CC
      • et al.
      Managing clonal hematopoiesis in patients with solid tumors.
      ], although not so much is known regarding the driver genes or molecular mechanisms involved therein. Nevertheless, it has been reported that cancer patients with CH have worse prognosis than the ones without CH [
      • Coombs CC
      • Zehir A
      • Devlin SM
      • et al.
      Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome.
      ,
      • Gibson CJ
      • Lindsley RC
      • Tchekmedyian V
      • et al.
      Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma.
      ]. Interestingly, CH-driver gene mutations have been identified in tumor-supporting lymphocytes and macrophages in the tumor stroma but not in the tumor epithelium. The same mutations were found in the blood cells of the same patients although at a lower VAF [
      • Kleppe M
      • et al.
      Somatic mutations in leukocytes infiltrating primary breast cancers.
      ].
      Although the exact relationship between CH, CVD and solid cancers is not yet clear, there is growing apprehension that CH may be a risk factor linking CVDs and cancer progression. Future studies using advanced sequencing technologies are awaited to shed light on the interrelationship between CH, cancer, and cardiovascular complications.

      Future perspectives on the role of CH in the development of atherosclerosis and CVDs

      CH has emerged as an age-dependent CRF although the underlying mechanisms are far from been completely understood. CH-driver gene mutations give an advantageous proliferation to specific HSC clones and promote monocytic skewing and increased production of inflammatory cytokines such as IL-1β and IL-6 and in this way accelerate inflammation in CVDs (Figure 3). The expansion of mutated HSC clones may be boosted by classic CRFs, considering evidence that hypercholesterolemia and diabetic conditions promote the expansion of HSCs and myelopoiesis. There may be a feedback loop in which CH induces inflammation and accelerates atherosclerosis, which in turn further stimulates the expansion of mutated HSPC clones and their progeny and further induces inflammatory responses and CVD progression (Figure 3).
      Figure 3
      Figure 3Schematic of a vicious circuit of inflammation driven by somatic mutations in myeloid blood cells. CH-driver gene mutations endorse an expansion of mutated HSC clones and empower myeloid skewing. Mutated myeloid cells have a pro-inflammatory profile that results in increased production of inflammatory cytokines, such as IL-1β, IL-6, and IL-8, which contribute to increased inflammation and acceleration of atherosclerosis and thrombosis, as well as a poor prognosis following degenerative aortic stenosis and heart failure. In turn, cardiovascular risk factors such as diabetes and hypercholesterolemia, by inducing the expression of inflammatory cytokines, can induce activation of HSCs and, by this vicious circuit, further promote the clonal dominance of mutated HSC clones, leading to a feedback loop between CHIP and CVDs.
      Mutations in different CH-driver genes result in different pro-inflammatory profiles, suggesting that the underlying mechanisms may be different. Thus, it is important to characterize the molecular mechanisms by which the various CH-driver gene mutations contribute to CVDs or other inflammatory diseases and cancer. Preclinical studies have reported that NLRP3 inhibitors that block IL-1β production can inhibit atherosclerosis in mice with TET2-deficient BM cells [
      • Sano S
      • Oshima K
      • Wang Y
      • et al.
      Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome.
      ]. Recently, the CANTOS clinical trial found that anti-inflammatory treatments using a neutralizing antibody against IL-1β improve CVD patient outcome and, in addition, lower total cancer mortality [
      • Ridker PM
      • Everett BM
      • Thuren T
      • et al.
      Antiinflammatory therapy with canakinumab for atherosclerotic disease.
      ,
      • Ridker PM
      • MacFadyen JG
      • Thuren T
      • et al.
      Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial.
      ]. In line with this, Bick and colleagues reported that individuals with CHIP and a genetic deficiency in IL-6 signaling (by carrying the IL6R p.Asp358Ala allele variant) had a decreased CVD risk compared with CHIP patients without defective IL-6 signaling [
      • Bick AG
      • Pirruccello JP
      • Griffin GK
      • et al.
      Genetic IL-6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis.
      ]. As targeted therapies against CHIP-driver gene products are technically more challenging to implement, it may be more effective to design therapies targeting their causal effects. Future approaches are likely to include a combination of anti-inflammatory treatments and clonal selective immunotherapies.
      The prevalence of CH is increasing in an aging population, as are the numbers of coding and non-coding driver events of CH. Not all mutations leading to CH will also have a consequence on the development and progression of CVDs. Future studies must delineate specific mutated genes and even distinct mutations in these genes that are truly associated with and clinically relevant for various diseases in the cardiovascular system having a high predictive value, as recently evidenced for the prediction of AML progression [
      • Abelson S
      • Collord G
      • Ng SWK
      • et al.
      Prediction of acute myeloid leukaemia risk in healthy individuals.
      ,
      • Sellar RS
      • Jaiswal S
      • Ebert BL
      Predicting progression to AML.
      ]. Careful evaluation of driver mutations, also within one particular gene, will help us to distinguish cooperating events from passenger events. Moreover, mechanistic studies, by generating functional mutation-specific models of these driver mutations, must be applied to identify the functional consequences of these mutations in the context of CVD to enlighten the causative effects that can be targeted in the future. Shared mechanisms of different mutated genes may be identified as common targets in the treatment of different CVDs.
      These recent findings have raised several questions for clinicians as well as for patients. Although screening of patients with a high prevalence of CHIP or hematological malignancies is well established, screening of CVD patients for the presence of predictive CHIP-driver mutations is not presently customary. Based on the association between CH and the development of CVDs, as well as the poor prognosis of patients with CVDs, it may be reasonable to screen individuals with CVDs for CHIP, especially individuals with CAD in the absence of traditional CRFs. Based on developments in the field of next-generation sequencing, genotyping for CH may become routine in the near future. In addition, a logical consequence would be to initiate a more intense screening for CVD blood parameters and echocardiography, angiography, or [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for people with CH mutations, and recommend lifestyle changes to reduce confounding factors.
      Despite the challenges, future studies are awaited to shed more light on the functional causalities of distinct CH-driver mutations and their associated diseases, including CVDs, and on the clinical management of complications associated with CH in these patients.

      Acknowledgments

      We acknowledge financial support from the German Research Foundation ( SFB 834 ; Project B6 [AMZ] and Project Z1 [MAR], the Excellence Cluster Cardio-Pulmonary Institute , and Project RI2462/1–1 [MAR]) and the German Center for Cardiovascular Research, DZHK, Berlin, Germany, partner site Rhine-Main.

      Conflict of interest disclosure

      The authors do not have any conflicts of interest to declare.

      References

        • Libby P.
        History of discovery: inflammation in atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2012; 32: 2045-2051
        • Pardali E
        • Waltenberger J.
        Monocyte function and trafficking in cardiovascular disease.
        Thromb Haemost. 2012; 108: 804-811
        • Dragoljevic D
        • Westerterp M
        • Veiga CB
        • Nagareddy P
        • Murphy AJ
        Disordered haematopoiesis and cardiovascular disease: a focus on myelopoiesis.
        Clin Sci (Lond). 2018; 132: 1889-1899
        • North BJ
        • Sinclair DA.
        The intersection between aging and cardiovascular disease.
        Circ Res. 2012; 110: 1097-1108
        • Fajemiroye JO
        • da Cunha LC
        • Saavedra-Rodríguez R
        • et al.
        Aging-induced biological changes and cardiovascular diseases.
        BioMed Res Int. 2018; 20187156435
        • Zhang W
        • Song M
        • Qu J
        • Liu GH
        Epigenetic modifications in cardiovascular aging and diseases.
        Circ Res. 2018; 123: 773-786
        • Zarzour A
        • Kim HW
        • Weintraub NL
        Epigenetic regulation of vascular diseases.
        Arterioscler Thromb Vasc Biol. 2019; 39: 984-990
        • Gallagher KA
        • Joshi A
        • Carson WF
        • et al.
        Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes.
        Diabetes. 2015; 64: 1420-1430
        • Sano S
        • Wang Y
        • Walsh K
        Clonal hematopoiesis and its impact on cardiovascular disease.
        Circ J. 2018; 83: 2-11
        • Libby P
        • Sidlow R
        • Lin AE
        • et al.
        Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week.
        J Am Coll Cardiol. 2019; 74: 567-577
        • Steensma DP
        • Bejar R
        • Jaiswal S
        • et al.
        Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.
        Blood. 2015; 126: 9-16
        • Olivares R
        • Ducimetière P
        • Claude JR
        Monocyte count: a risk factor for coronary heart disease?.
        Am J Epidemiol. 1993; 137: 49-53
        • Johnsen SH
        • et al.
        Monocyte count is a predictor of novel plaque formation: a 7-year follow-up study of 2610 persons without carotid plaque at baseline the Tromsø Study.
        Stroke. 2005; 36: 715-719
        • Ylitalo R
        • Oksala O
        • Ylä-Herttuala S
        • Ylitalo P
        Effects of clodronate (dichloromethylene bisphosphonate) on the development of experimental atherosclerosis in rabbits.
        J Lab Clin Med. 1994; 123: 769-776
        • Stoneman V
        • et al.
        Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques.
        Circ Res. 2007; 100: 884-893
        • Rajavashisth T
        • Qiao JH
        • Tripathi S
        • et al.
        Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor-deficient mice.
        J Clin Invest. 1998; 101: 2702-2710
        • Bannon P
        • Wood S
        • Restivo T
        • Campbell L
        • Hardman MJ
        • Mace KA
        Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice.
        Dis Model Mech. 2013; 6: 1434-1447
        • Potteaux S
        • Gautier EL
        • Hutchison SB
        • et al.
        Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe–/– mice during disease regression.
        J Clin Invest. 2011; 121: 2025-2036
        • Nagareddy PR
        • Murphy AJ
        • Stirzaker RA
        • et al.
        Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.
        Cell Metab. 2013; 17: 695-708
        • Nagareddy PR
        • Kraakman M
        • Masters SL
        • et al.
        Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity.
        Cell Metab. 2014; 19: 821-835
        • Swirski FK
        • Libby P
        • Aikawa E
        • et al.
        Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata.
        J Clin Invest. 2007; 117: 195-205
        • Murphy AJ
        • Dragoljevic D
        • Tall AR
        Cholesterol efflux pathways regulate myelopoiesis: a potential link to altered macrophage function in atherosclerosis.
        Front Immunol. 2014; 5: 490
        • Murphy AJ
        • Akhtari M
        • Tolani S
        • et al.
        ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice.
        J Clin Invest. 2011; 121: 4138-4149
        • Tall AR
        • Yvan-Charvet L.
        Cholesterol, inflammation and innate immunity.
        Nat Rev Immunol. 2015; 15: 104-116
        • Tolani S
        • Pagler TA
        • Murphy AJ
        • et al.
        Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: studies in mice and FH children.
        Atherosclerosis. 2013; 229: 79-85
        • Dragoljevic D
        • Kraakman MJ
        • Nagareddy PR
        • et al.
        Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis.
        Eur Heart J. 2018; 39: 2158-2167
        • Ferraro F
        • Lymperi S
        • Méndez-Ferrer S
        • et al.
        Diabetes impairs hematopoietic stem cell mobilization through alteration of niche function.
        Sci Transl Med. 2011; 3: 104ra101
        • Hazra S
        • Jarajapu YPR
        • Stepps V
        • et al.
        Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model.
        Diabetologia. 2013; 56: 644-653
        • Orlandi A
        • Chavakis E
        • Seeger F
        • Tjwa M
        • Zeiher AM
        • Dimmeler S
        Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice.
        Basic Res Cardiol. 2010; 105: 703-712
        • Jaiswal S
        • Natarajan P
        • Ebert BL
        Clonal hematopoiesis and atherosclerosis.
        N Engl J Med. 2017; 377: 1401-1402
        • Jaiswal S
        • Fontanillas P
        • Flannick J
        • et al.
        Age-related clonal hematopoiesis associated with adverse outcomes.
        N Engl J Med. 2014; 371: 2488-2498
        • Jaiswal S
        • Natarajan P
        • Silver AJ
        • et al.
        Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
        N Engl J Med. 2017; 377: 111-121
        • Genovese G
        • Kahler AK
        • Handsaker RE
        • et al.
        Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
        N Engl J Med. 2014; 371: 2477-2487
        • Welch JS
        • Ley TJ
        • Link DC
        • et al.
        The origin and evolution of mutations in acute myeloid leukemia.
        Cell. 2012; 150: 264-278
        • Bowman RL
        • Busque L
        • Levine RL
        Clonal hematopoiesis and evolution to hematopoietic malignancies.
        Cell Stem Cell. 2018; 22: 157-170
        • Beerman I
        • Bhattacharya D
        • Zandi S
        • et al.
        Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion.
        Proc Natl Acad Sci USA. 2010; 107: 5465-5470
        • Busque L
        • Mio R
        • Mattioli J
        • et al.
        Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age.
        Blood. 1996; 88: 59-65
        • Fey MF
        • Liechti-Gallati S
        • von Rohr A
        • et al.
        Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe.
        Blood. 1994; 83: 931-938
        • Gale RE
        • Fielding AK
        • Harrison CN
        • Linch DC
        Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age.
        Br J Haematol. 1997; 98: 512-519
        • Busque L
        • Patel JP
        • Figueroa M
        • et al.
        Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis.
        Nat Genet. 2012; 44: 1179-1181
        • Delhommeau F
        • Dupont S
        • Della Valle V
        • et al.
        Mutation in TET2 in myeloid cancers.
        N Engl J Med. 2009; 360: 2289-2301
        • Xie M
        • Lu C
        • Wang J
        • et al.
        Age-related cancer mutations associated with clonal hematopoietic expansion.
        Nat Med. 2014; 20: 1472-1478
        • Coombs CC
        • Zehir A
        • Devlin SM
        • et al.
        Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome.
        Cell Stem Cell. 2017; 21 (e4): 374-382
        • Papaemmanuil E
        • Gerstung M
        • Bullinger L
        • et al.
        Genomic classification and prognosis in acute myeloid leukemia.
        N Engl J Med. 2016; 374: 2209-2221
        • Abelson S
        • Collord G
        • Ng SWK
        • et al.
        Prediction of acute myeloid leukaemia risk in healthy individuals.
        Nature. 2018; 559: 400-404
        • Young AL
        • Challen GA
        • Birmann BM
        • Druley TE
        Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.
        Nat Commun. 2016; 7: 12484
        • Shlush LI
        • Zandi S
        • Mitchell A
        • et al.
        Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.
        Nature. 2014; 506: 328-333
        • McKerrell T
        • Park N
        • Moreno T
        • et al.
        Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis.
        Cell Rep. 2015; 10: 1239-1245
        • Acuna-Hidalgo R
        • Sengul H
        • Steehouwer M
        • et al.
        Ultra-sensitive sequencing identifies high prevalence of clonal hematopoiesis-associated mutations throughout adult life.
        Am J Hum Genet. 2017; 101: 50-64
        • 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: 25-33
        • Mas-Peiro S
        • Hoffmann J
        • Fichtlscherer S
        • et al.
        Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation.
        Eur Heart J. 2019; (Epub ahead of print)https://doi.org/10.1093/eurheartj/ehz591
        • Carobbio A
        • Finazzi G
        • Guerini V
        Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status.
        Blood. 2007; 109: 2310-2313
        • Marchioli R
        • Finazzi G
        • Marfisi RM
        • Tognoni G
        • Barbui T
        Clinical trials in myeloproliferative disorders: looking forward.
        Semin Hematol. 2005; 42: 259-265
        • Wolach O
        • Sellar RS
        • Marinod K
        • et al.
        Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms.
        Sci Transl Med. 2018; 10
        • Ko M
        • Huang Y
        • Jankowska AM
        • et al.
        Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.
        Nature. 2010; 468: 839-843
        • Ko M
        • Bandukwala HS
        • An J
        • et al.
        Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice.
        Proc Natl Acad Sci USA. 2011; 108: 14566-14571
        • Li Z
        • Cai X
        • Cai CL
        • et al.
        Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies.
        Blood. 2011; 118: 4509-4518
        • Langemeijer SM
        • Kuiper RP
        • Berends M
        • et al.
        Acquired mutations in TET2 are common in myelodysplastic syndromes.
        Nat Genet. 2009; 41: 838-842
        • Dorsheimer L
        • Assmus B
        • Rasper T
        • et al.
        Hematopoietic alterations in chronic heart failure patients by somatic mutations leading to clonal hematopoiesis: CHIP-related hematopoietic alterations in CHF patients.
        Haematologica. 2019; (Epub ahead of print)https://doi.org/10.3324/haematol.2019.224402
        • Fuster JJ
        • MacLauchlan S
        • Zuriaga MA
        • et al.
        Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
        Science. 2017; 355: 842-847
        • Zhang Q
        • Zhao K
        • Shen Q
        • et al.
        Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6.
        Nature. 2015; 525: 389-393
        • Sano S
        • Oshima K
        • Wang Y
        • et al.
        Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome.
        J Am Coll Cardiol. 2018; 71: 875-886
        • 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: 335-341
        • Yue X
        • Lio CWJ
        • Samaniego-Castruita D
        • Li X
        • Rao A
        Loss of TET2 and TET3 in regulatory T cells unleashes effector function.
        Nat Commun. 2019; 10: 2011
        • Buscarlet M
        • Provost S
        • Zada YF
        • et al.
        Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A.
        Blood. 2018; 132: 277-280
        • Zhang X
        • Su J
        • Jeong M
        • et al.
        DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells.
        Nat Genet. 2016; 48: 1014-1023
        • Cole CB
        • Russler-Germain DA
        • Ketkar S
        • et al.
        Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies.
        J Clin Invest. 2017; 127: 3657-3674
        • Challen GA
        • Sun D
        • Jeong M
        • et al.
        Dnmt3a is essential for hematopoietic stem cell differentiation.
        Nat Genet. 2011; 44: 23-31
        • Gamper CJ
        • Agoston AT
        • Nelson WG
        • Powell JD
        Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation.
        J Immunol. 2009; 183: 2267-2276
        • Leoni C
        • Montagner S
        • Rinaldi A
        • et al.
        Dnmt3a restrains mast cell inflammatory responses.
        Proc Natl Acad Sci USA. 2017; 114: E1490-E1499
        • Li X
        • Zhang Q
        • Ding Y
        • et al.
        Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity.
        Nat Immunol. 2016; 17: 806-815
        • Pham D
        • Walline CC
        • Hollister K
        • et al.
        The transcription factor Twist1 limits T helper 17 and T follicular helper cell development by repressing the gene encoding the interleukin-6 receptor α chain.
        J Biol Chem. 2013; 288: 27423-27433
        • Yu Q
        • Zhou B
        • Zhang Y
        • et al.
        DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation.
        Proc Natl Acad Sci USA. 2012; 109: 541-546
        • Ma Y
        • Yuan X
        • Deng L
        • et al.
        Imbalanced frequencies of Th17 and Treg cells in acute coronary syndromes are mediated by IL-6-STAT3 signaling.
        PloS One. 2013; 8: e72804
        • Park SO
        • Wamsley HL
        • Bae K
        • et al.
        Conditional deletion of Jak2 reveals an essential role in hematopoiesis throughout mouse ontogeny: implications for Jak2 inhibition in humans.
        PloS One. 2013; 8: e59675
        • Kirabo A
        • Embury J
        • Kiss R
        • et al.
        The stilbenoid tyrosine kinase inhibitor, G6, suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo.
        J Biol Chem. 2011; 286: 4280-4291
        • Sivasubramaniyam T
        • Schroer SA
        • Li A
        • et al.
        Hepatic JAK2 protects against atherosclerosis through circulating IGF-1.
        JCI Insight. 2017; 2: e93735
        • Xavier SG
        • Gadelha T
        • Rezende SM
        • Zalcberg IR
        • Spector N
        JAK2V617F mutation in patients with thrombosis.
        To screen or not to screen? Int J Lab Hematol. 2011; 33: 117-124
        • Lundberg P
        • Takizawa H
        • Kubocakova L
        • et al.
        Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F.
        J Exp Med. 2014; 211: 2213-2230
        • Okugawa S
        • Ota Y
        • Kitazawa T
        • et al.
        Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages.
        Am J Physiol Cell Physiol. 2003; 285: C399-C408
        • Oku S
        • Takenaka K
        • Kuriyama T
        • et al.
        JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation.
        Br J Haematol. 2010; 150: 334-344
        • Wang W
        • Liu W
        • Fidler T
        • et al.
        Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 V617F mice.
        Circ Res. 2018; 123: e35-e47
        • de Boer RA
        • Meijers WC
        • van der Meer P
        • van Veldhuisen DJ
        Cancer and heart disease: associations and relations.
        Eur J Heart Failure. 2019; 21: 1515-1525
        • Totzeck M
        • Schuler M
        • Stuschke M
        • Heusch G
        • Rassaf T
        Cardio-oncology—strategies for management of cancer-therapy related cardiovascular disease.
        Int J Cardiol. 2019; 280: 163-175
        • Koene RJ
        • Prizment AE
        • Blaes A
        • Konety SH
        Shared risk factors in cardiovascular disease and cancer.
        Circulation. 2016; 133: 1104-1114
        • Kuper H
        • Adami HO
        • Trichopoulos D
        Infections as a major preventable cause of human cancer.
        J Intern Med. 2000; 248: 171-183
        • Greten FR
        • Grivennikov SI.
        Inflammation and cancer: triggers, mechanisms, and consequences.
        Immunity. 2019; 51: 27-41
        • Crusz SM
        • Balkwill FR
        Inflammation and cancer: advances and new agents.
        Nat Rev Clin Oncol. 2015; 12: 584-596
        • Vincent L
        • Leedy D
        • Masri SC
        • Cheng RK
        Cardiovascular disease and cancer: is there increasing overlap?.
        Curr Oncol Rep. 2019; 21: 47
        • Meijers WC
        • de Boer RA
        Common risk factors for heart failure and cancer.
        Cardiovasc Res. 2019; 115: 844-853
        • Brunner AM
        • Blonquist TM
        • Hobbs GS
        • et al.
        Risk and timing of cardiovascular death among patients with myelodysplastic syndromes.
        Blood Adv. 2017; 1: 2032-2040
        • van Leeuwen FE
        • Ng AK
        Long-term risk of second malignancy and cardiovascular disease after Hodgkin lymphoma treatment.
        Hematology. 2016; 2016: 323-330
        • van Haelst PL
        • Schot B
        • Hoendermis ES
        • van den Berg MP
        Acute myeloid leukaemia as a cause of acute ischaemic heart disease.
        Neth Heart J. 2006; 14: 62-65
        • Navi BB
        • Reiner AS
        • Kamel H
        • et al.
        Risk of arterial thromboembolism in patients with cancer.
        J Am Coll Cardiol. 2017; 70: 926-938
        • Navi BB
        • Reiner AS
        • Kamel H
        • et al.
        Arterial thromboembolic events preceding the diagnosis of cancer in older persons.
        Blood. 2019; 133: 781-789
        • Wang SC
        • Schulman-Marcus J
        • Fantauzzi J
        • et al.
        Colon cancer laterality is associated with atherosclerosis and coronary artery disease.
        J Gastrointest Oncol. 2019; 10: 30-36
        • Rinde LB
        • Småbrekke B
        • Hald EM
        • et al.
        Myocardial infarction and future risk of cancer in the general population—the Tromsø Study.
        Eur J Epidemiol. 2017; 32: 193-201
        • Bolton KL
        • Gillis NK
        • Coombs CC
        • et al.
        Managing clonal hematopoiesis in patients with solid tumors.
        J Clin Oncol. 2019; 37: 7-11
        • Gibson CJ
        • Lindsley RC
        • Tchekmedyian V
        • et al.
        Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma.
        J Clin Oncol. 2017; 35: 1598-1605
        • Kleppe M
        • et al.
        Somatic mutations in leukocytes infiltrating primary breast cancers.
        NPJ Breast Cancer. 2015; 1: 15005
        • Ridker PM
        • Everett BM
        • Thuren T
        • et al.
        Antiinflammatory therapy with canakinumab for atherosclerotic disease.
        N Engl J Med. 2017; 377: 1119-1131
        • Ridker PM
        • MacFadyen JG
        • Thuren T
        • et al.
        Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial.
        Lancet. 2017; 390: 1833-1842
        • Bick AG
        • Pirruccello JP
        • Griffin GK
        • et al.
        Genetic IL-6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis.
        Circulation. 2019; (Epub ahead of print)https://doi.org/10.1161/circulation/aha.119.044362
        • Sellar RS
        • Jaiswal S
        • Ebert BL
        Predicting progression to AML.
        Nat Med. 2018; 24: 904-906