Association of Clonal Hematopoiesis With Incident Heart Failure

Yu, Bing; Roberts, Mary B.; Raffield, Laura M.; Zekavat, Seyedeh M.; Nguyen, Ngoc Quynh; Biggs, Mary L.; Brown, M. R. W.; Griffin, Gabriel K.; Desai, Pinkal; Correa, Adolfo; Morrison, Alanna C.; Shah, Amil M.; Niroula, Abhishek; Uddin, Md Mesbah; Honigberg, Michael C.; Ebert, Benjamin L.; Psaty, Bruce M.; Whitsel, Eric A.; Manson, Jo Ann E.; Kooperberg, Charles; Bick, Alexander; Ballantyne, Christie M.; Reiner, Alex P.; Natarajan, Pradeep; Eaton, Charles B.

doi:10.1016/j.jacc.2021.04.085

Cited by 140 publications

(114 citation statements)

References 36 publications

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“…These exploratory analyses were based on reports of kidney damage in mouse models having TET2 or DNMT3A variants 15,22 and on data suggesting a dose-response-association between VAF and cardiovascular outcome. [16][17][18] Although we could not find an effect of CHIP, strong known risk factors such as albuminuria, higher HbA1c, heart failure, and smoking 1 were associated with kidney function decline in our cohort. It has been suggested that CHIP increases cardiovascular risk via endothelial inflammation that promotes atherogenesis.…”

Section: Discussioncontrasting

confidence: 73%

“…These findings are in line with previously published data. 7,49 Multiple studies indicate an increased cardiovascular risk in CHIP 11,[15][16][17][18][19][20][21] , presumably via increased microinflammation. Marked glomerulosclerosis and increased kidney fibrosis when challenged with angiotensin II were described in mouse models representing a setting with TET2 and DNMT3A variants 15,22 .…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] As somatic variants accumulate in different cell types throughout life 14 , the prevalence of CHIP increases considerably with advancing age. [11][12][13] In previous studies the presence of CHIP has been associated with increased risk of coronary heart disease, ischemic stroke and heart failure 11,[15][16][17] as well as adverse outcomes in patients with heart failure [18][19][20] or degenerative aortic valve stenosis. 21 Experimental data suggest endothelial as well as tissue inflammation and fibrosis via clonally-derived macrophages and monocytes as possible mechanisms behind adverse outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study

Denicolò

Vogi

Keller

et al. 2022

Kidney International Reports

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Section: Discussioncontrasting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study

Denicolò

Vogi

Keller

et al. 2022

Kidney International Reports

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“…In a cohort of individuals with ischemic heart failure (HF), Dorsheimer and others (Dorsheimer et al, 2020) observed an association between CHIP, due to mutations in DNMT3A and TET2 genes, with a marked increase in the number of hospitalizations and risk of death from HF. These observations, though from a smaller number of patients, tend to support the involvement of CHIP not only in the pathogenesis of MI and stroke, but also in HF prognosis (Yu et al, 2021). In tandem with aging, the prevalence of comorbidity increases in patients with chronic HF and nearly half of patients with HF have five or more comorbidities associated with a pro-inflammatory state.…”

Section: Ch/chip Mutations and Their Relationships To Aging Conditionsmentioning

confidence: 71%

Clonal Hematopoiesis Analyses in Clinical, Epidemiologic, and Genetic Aging Studies to Unravel Underlying Mechanisms of Age-Related Dysfunction in Humans

et al. 2022

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Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that expand with age in otherwise normal tissues. In the hematopoietic system, this phenomenon has generally been referred to as “clonal hematopoiesis of indeterminate potential” (CHIP) when it applies to a subset of clones in which mutations in driver genes of hematologic malignancies are found. Other mechanisms of clonal hematopoiesis, including large chromosomal alterations, can also give rise to clonal expansion in the absence of conventional CHIP driver gene mutations. Both types of clonal hematopoiesis (CH) have been observed in studies of animal models and humans in association with altered immune responses, increased mortality, and disease risk. Studies in murine models have found that some of these clonal events are involved in abnormal inflammatory and metabolic changes, altered DNA damage repair and epigenetic changes. Studies in long-lived individuals also show the accumulation of somatic mutations, yet at this advanced age, carriership of somatic mutations is no longer associated with an increased risk of mortality. While it remains to be elucidated what factors modify this genotype-phenotype association, i.e., compensatory germline genetics, cellular context of the mutations, protective effects to diseases at exceptional age, it points out that the exceptionally long-lived are key to understand the phenotypic consequences of CHIP mutations. Assessment of the clinical significance of somatic mutations occurring in blood cell types for age-related outcomes in human populations of varied life and health span, environmental exposures, and germline genetic risk factors will be valuable in the development of personalized strategies tailored to specific somatic mutations for healthy aging.

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“…Clone size, as estimated by VAF, is strongly associated with the prognosis of CHIP, whether it be cancer, subclinical atherosclerosis, atherosclerotic CVD, or heart failure 13,20,21,61,62 . Thus, identifying CHIP early will provide a window of opportunity to slow clonal growth and avoid CV complications.…”

Section: Accelerators Of Chipmentioning

confidence: 99%

Hematopoiesis of Indeterminate Potential and Atherothrombotic Risk

et al. 2022

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Haematopoiesis is the process of blood production, essential for the continued supply of immune cells and red blood cells. However, the proliferative nature of haematopoietic stem cell (HSCs) renders them susceptible to developing somatic mutations. HSCs carrying a mutation can gain a selective advantage compared to normal HSCs and result in haematological disorders. One such disorder is termed clonal haematopoiesis of indeterminate potential (CHIP), a pre-malignant state associated with ageing, where the mutant HSCs are responsible for producing a small portion of the mature immune cells in the circulation and subsequently in tissues. People with CHIP have been shown to have an increased risk of mortality due to cardiovascular disease (CVD). Why this occurs is under rigorous investigation, but the majority of the studies to date suggest increased atherosclerosis is due to heightened inflammatory cytokine release from mutant lesional macrophages. However, given CHIP is driven by several mutations, other haematopoietic lineages can be altered to promote CVD. In this review we explore the relationship between mutations in genes causing CHIP and atherothrombotic disorders, along with potential mechanisms of enhanced clonal outgrowth and potential therapies and strategies to slow CHIP progression.

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Association of Clonal Hematopoiesis With Incident Heart Failure

Cited by 140 publications

References 36 publications

Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study

Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study

Clonal Hematopoiesis Analyses in Clinical, Epidemiologic, and Genetic Aging Studies to Unravel Underlying Mechanisms of Age-Related Dysfunction in Humans

Hematopoiesis of Indeterminate Potential and Atherothrombotic Risk

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