Multiple Somatic Mutations for Clonal Hematopoiesis Are Associated With Increased Mortality in Patients With Chronic Heart Failure

Cremer, Sebastian; Kirschbaum, Klara; Berkowitsch, Alexander; John, David; Kiefer, Katharina; Dorsheimer, Lena; Wagner, Jasmin; Rasper, Tina; Abou-El-Ardat, Khalil; Aßmus, Birgit; Rieger, Michael A.; Dimmeler, Stefanie; Zeiher, Andreas M.

doi:10.1161/circgen.120.003003

Cited by 42 publications

(26 citation statements)

References 5 publications

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“…The results of this experimental study are supported by a recent study that found an association between PPM1D -mediated clonal hematopoiesis and worse outcome in chronic ischemic heart failure. 27 Collectively, these findings raise the possibility that PPM1D -mediated t-CH may be a factor that contributes to the development of late-onset heart failure in cancer survivors.…”

Section: Discussionmentioning

confidence: 91%

The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice

Yura

Miura‐Yura

Min

et al. 2021

Circulation Research

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Rationale: Cancer therapy can be associated with short- and long-term cardiac dysfunction. Cancer patients often exhibit therapy-related clonal hematopoiesis (t-CH), an aggressive form of clonal hematopoiesis that can result from somatic mutations in genes encoding regulators of the DNA-damage response (DDR) pathway. Gain-of-function mutations in exon 6 the protein phosphatase Mg2+/Mn2+ dependent 1D (PPM1D) gene are the most frequently mutated DDR gene associated with t-CH. Whether t-CH can contribute to cardiac dysfunction is unknown. Objective: We evaluated the causal and mechanistic relationships between Ppm1d-mediated t-CH and non-ischemic heart failure in an experimental system. Methods and Results: To test whether gain-of-function hematopoietic cell mutations in Ppm1d can increase the susceptibility to cardiac stress, we evaluated cardiac dysfunction in a mouse model where clonal hematopoiesis-associated mutations in exon 6 of Ppm1d were produced by CRISPR-Cas9 technology. Mice transplanted with hematopoietic stem cells containing the mutated Ppm1d gene exhibited augmented cardiac remodeling following the continuous infusion of angiotensin II (AngII). Ppm1d-mutant macrophages were impaired in DDR pathway activation and displayed greater DNA damage, higher reactive oxygen species generation and an augmented proinflammatory profile with elevations in IL-1β and IL-18. The administration of an NLRP3 inflammasome inhibitor to mice reversed the cardiac phenotype induced by the Ppm1d-mutated hematopoietic stem cells under conditions of AngII-induced stress. Conclusions: A mouse model of Ppm1d-mediated t-CH was more susceptible to cardiac stress. Mechanistically, disruption of the DDR pathway led to elevations in inflammatory cytokine production, and the NLRP3 inflammasome was shown to be essential for this augmented cardiac stress response. These data indicate that t-CH involving activating mutations in PPM1D can contribute to the cardiac dysfunction observed in cancer survivors, and that anti-inflammatory therapy may have utility in treating this condition.

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Section: Discussionmentioning

confidence: 91%

The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice

Yura

Miura‐Yura

Min

et al. 2021

Circulation Research

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“…Association of TET2 with CVD was demonstrated in the same studies that implicated cardiovascular connection of DNMT3A [10,[30][31][32][33]. In addition, recent data indicate that patients with chronic heart failure harboring both TET2 and DNMT3A mutations are at higher mortality risk than single mutation carriers [45].…”

Section: Tet2mentioning

confidence: 73%

“…Since Tet2 deficiency in macrophages results in overproduction of the pro-inflammatory and pro-atherogenic cytokine IL-1β [51], accelerated plaque growth, and increased risks of heart failure in mouse models [45], this raises the possibility that the blockade of IL-1β or its receptor may be effective therapy in individuals with TET2 mutations. In support of this, targeting the interleukin-1β in the CANTOS trial with an IL-1β-neutralizing antibody canakinumab significantly lowered the risk of recurrent cardiovascular events [94].…”

Section: Potential Therapeutic Interventions For Ch-related Conditionsmentioning

confidence: 99%

Clonal Hematopoiesis, Cardiovascular Diseases and Hematopoietic Stem Cells

Кандараков

Belyavsky

2020

IJMS

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Cardiovascular diseases and cancer, the leading causes of morbidity and mortality in the elderly, share some common mechanisms, in particular inflammation, contributing to their progression and pathogenesis. However, somatic mutagenesis, a driving force in cancer development, has not been generally considered as an important factor in cardiovascular disease pathology. Recent studies demonstrated that during normal aging, somatic mutagenesis occurs in blood cells, often resulting in expansion of mutant clones that dominate hematopoiesis at advanced age. This clonal hematopoiesis is primarily associated with mutations in certain leukemia-related driver genes and, being by itself relatively benign, not only increases the risks of subsequent malignant hematopoietic transformation, but, unexpectedly, has a significant impact on progression of atherosclerosis and cardiovascular diseases. In this review, we discuss the phenomenon of clonal hematopoiesis, the most important genes involved in it, its impact on cardiovascular diseases, and relevant aspects of hematopoietic stem cell biology.

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“…Cremer et al [ 25 ] analyzed 419 patients with chronic heart failure and reported a total of 223 mutations in 154 of 419 patients in their study. Mutations were most commonly found in DNMT3A and TET2.…”

Section: Resultsmentioning

confidence: 99%

“…They reported that patients with mutations in either DNMT3A or TET2 exhibited an accelerated HF progression in terms of death (hazard ratio: 2.79). Cremer et al [25] analyzed 419 patients with chronic heart failure and reported a total of 223 mutations in 154 of 419 patients in their study. Mutations were most commonly found in DNMT3A and TET2.…”

Section: Description About the Studiesmentioning

confidence: 99%

Clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular diseases—an updated systematic review

Senguttuvan

Subramanian

Venkatesan

et al. 2021

Journal of Genetic Engineering and Biotechnology

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Background Cardiovascular diseases (CVDs) are the leading cause of mortality in India. Residual risk exists in patients receiving optimal guideline-directed medical therapy. Possession of certain somatic mutations, at a variant allele frequency of ≥ 2% in peripheral blood, driving clonal expansion in the absence of cytopenias and dysplastic hematopoiesis is defined as clonal hematopoiesis of indeterminate potential (CHIP). Recently, it was found that carriers of CHIP had a higher risk to have coronary artery disease (CAD) and early-onset myocardial infarction. Association of CHIP with heart failure and valvular heart diseases is increasingly being considered. The common link that connects CHIP mutations and CVDs is inflammation leading to increased expression of cytokines and chemokines. We intended to do a systematic review about the association of CHIP mutations and CVD along with identifying specific CHIP mutations involved in increasing the risk of having CVDs. The main body of the abstract We performed an extensive literature search in PubMed and Google Scholar databases. Out of 302 articles, we narrowed it down to 10 studies based on our pre-specified criteria. The methodology adopted for the identification of CHIP mutations in the selected studies included – whole-exome sequencing (n = 3), whole-genome analysis (n = 1), transcriptome profiling analysis (n = 1), whole-genome analysis (n = 1), and single-cell RNA-sequencing (n = 1). We found that the available literature suggested an association between CHIP and CVD. The most commonly described CHIP mutations in patients with CVD are DNMT3A, TET2, ASXL1, TP53, JAK2, and SF3B. We further analyzed the commonly mutated CHIP genes using bioinformatics tools. Protein function and interaction analysis were performed using the g: Profiler and GeneMANIA online tools. The results revealed significant bio grid interactions for molecular functions, biological processes, and biological pathways. Interaction analysis showed significant physical and co-expression interactions. Short conclusion We conclude that there exists a significant association between CHIP mutations and CVD with DNMT3A, TET2, ASXL1, TP53, JAK2, and SF3B as the commonly implicated genes. The recognition of the link between CHIP and cardiovascular events will expand our understanding of residual risk and will open up new avenues of investigation and therapeutic modalities in the management of patients with CVD.

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Multiple Somatic Mutations for Clonal Hematopoiesis Are Associated With Increased Mortality in Patients With Chronic Heart Failure

Cited by 42 publications

References 5 publications

The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice

The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice

Clonal Hematopoiesis, Cardiovascular Diseases and Hematopoietic Stem Cells

Clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular diseases—an updated systematic review

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