Clonal haematopoiesis of indeterminate potential: associations with heart failure incidence, clinical parameters and biomarkers

Shi, Canxia; Aboumsallem, Joseph Pierre; Suthahar, Navin; Graaf, Aniek O. de; Jansen, Joop H.; Zeventer, Isabelle A van; Bračun, Valentina; Wit, Sanne de; Screever, Elles M.; Berg, Pieter F. van den; Meijers, Wouter C.; Gansevoort, Ron T.; Bakker, Stephan J. L.; Harst, Pim van der; Silljé, Herman H W; Huls, Gerwin; Boer, Rudolf A. de

doi:10.1002/ejhf.2715

Cited by 25 publications

(19 citation statements)

References 43 publications

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“…16 Yu et al 17 found that CH, particularly with mutations in the ASXL1 , TET2 , and JAK2 driver genes, was associated with incident HF in an analysis of 5 large biobanks. More recently, the study by Shi et al 27 focused specifically on the role of CH in incident HFpEF. This study reported that CH, using a VAF threshold of 2%, was associated with incident HFpEF in individuals younger than 65 years, but this association was not found when the entire cohort was analyzed.…”

Section: Discussionmentioning

confidence: 99%

Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction

Cochran,

Yura,

Thel

et al. 2023

Circulation

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BACKGROUND: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. METHODS: Using a panel of 20 candidate CH driver genes and a variant allele frequency cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). RESULTS: Compared with controls, there was an enrichment of TET2 -mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P =0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e′ (14.9 versus 11.7, respectively; P =0.0096) and E/A (1.69 versus 0.89, respectively; P =0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of 59 individuals with HFpEF. In accordance, patients with HFpEF with CH and age ≥70 years exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P =0.042) compared with patients with HFpEF without CH and age ≥70 years. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2 –wild-type or Tet2 -deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (N ω -nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2 -CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e′ and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2 –wild-type condition. CONCLUSIONS: CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2 -mediated CH displays greater features of HFpEF.

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Section: Discussionmentioning

confidence: 99%

Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction

Cochran,

Yura,

Thel

et al. 2023

Circulation

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“…Several factors may favour development of heart failure (HF) 1,2 . Shi et al 3 . assessed the association between clonal haematopoiesis of indeterminate potential (CHIP) and incident HF.…”

Section: Pathophysiologymentioning

confidence: 99%

“…

Several factors may favour development of heart failure (HF). 1,2 Shi et al 3 assessed the association between clonal haematopoiesis of indeterminate potential (CHIP) and incident HF. A total of 374 participants with incident HF from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort were matched 1:1 by age and sex with healthy controls.

…”

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confidence: 99%

January 2023 at a glance: focus on acute heart failure and medical therapy

Tomasoni

Adamo

Metra

2023

European J of Heart Fail

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Several factors may favour development of heart failure (HF). 1,2 Shi et al. 3 assessed the association between clonal haematopoiesis of indeterminate potential (CHIP) and incident HF. A total of 374 participants with incident HF from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort were matched 1:1 by age and sex with healthy controls. The frequency of CHIP was overlapping between the two groups and CHIP was not significantly associated with incident HF at multivariable Cox regression models. However, the association was modified by age (p for interaction = 0.002) and CHIP was more frequent in the case cohort compared to controls among those younger than 65 years.Miranda et al. 4 compared exercise haemodynamics between 24 adult patients post-Fontan palliation, 48 patients with HF and preserved ejection fraction (HFpEF) and 48 subjects with non-cardiac dyspnoea (NCD). Resting and exercise pulmonary artery wedge pressure (PAWP) was lower in the Fontan group than HFpEF, but higher than NCD. However, there were no differences in ΔPAWP/ΔQs ratios between post-Fontan and HFpEF patients. Acute heart failureAcute heart failure (AHF) has a dramatic burden in terms of symptoms, morbidity and mortality. [5][6][7][8] Lee et al. 9 investigated the relationship between patient-reported symptoms, evaluated by the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) (range 0-100; 0 worst), and pulmonary congestion, assessed by lung ultrasound, physical examination and chest X-ray, in patients with AHF. A lower KCCQ-TSS was associated with worse New York Heart Association functional class and peripheral oedema but not with pulmonary congestion.Intravenous diuretics are the first option for the treatment of congestion in patients with AHF. Data regarding the optimal strategy of their administration are limited. 10,11 Their early administration is often considered as crucial. Among 15 078 patients included in the REPORT-HF registry from seven regions of the world, the median time-to-diuretics was 67 min. Time-to-diuretic administration did not have an impact on in-hospital mortality, but was associated with an increase in mortality risk at 30 days, especially in patients at higher risk. 12

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“…50 A recent case-controlled study in a well characterized general European population cohort [the Prevention of Renal and Vascular End-stage Disease (PREVEND) study] represented by 705 individuals successfully analyzed by error-corrected NGS for acquired mutations at a variant allele function of at least 2% in 27 CHIP driver genes demonstrated that the somatic mutations in clonal hematopoiesis positively correlated with heart failure risk factors and cardiovascular biomarkers, including N-terminal pro-B-type natriuretic peptide, and are associated with heart failure incidence mainly in individuals younger than 65 years. 55 In several clinical studies, somatic mutations that drive clonal hematopoiesis were commonly found among heart failure patients and are associated with meaningful effects on accelerated heart failure progression and a worse outcome. [56][57][58][59][60][61] Although heart failure in humans has various causes, different pathophysiological mechanisms and heterogeneous clinical manifestations, the experimental and clinical data reported above support the relevance of inflammatory cytokine production and signaling by immune cells in the pathogenesis of cardiac dysfunction and heart failure.…”

Section: Clonal Hematopoiesis Of Undetermined Significance In Heart F...mentioning

confidence: 99%

Clonal hematopoiesis of indeterminate potential: implications for the cardiologists

Sciatti,

D’Elia,

Gori

et al. 2023

Journal of Cardiovascular Medicine

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Myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are characterized by somatic gene mutations in bone marrow stem cells, which trigger an inflammatory response influencing the development of associated cardiovascular complications. In recent years, the same mutations were found in individuals with cardiovascular diseases even in the absence of hematological alterations. These genetic events allow the identification of a new entity called ‘clonal hematopoiesis of indeterminate potential’ (CHIP), as it was uncertain whether it could evolve toward hematological malignancies. CHIP is age-related and, remarkably, myocardial infarction, stroke, and heart failure were frequently reported in these individuals and attributed to systemic chronic inflammation driven by the genetic mutation. We reviewed the connection between clonal hematopoiesis, inflammation, and cardiovascular diseases, with a practical approach to improve clinical practice and highlight the current unmet needs in this area of knowledge.

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Clonal haematopoiesis of indeterminate potential: associations with heart failure incidence, clinical parameters and biomarkers

Abstract: We aimed to analyse the association of clonal haematopoiesis of indeterminate potential (CHIP) with incident heart failure (HF) in a European population cohort.

Cited by 25 publications

References 43 publications

Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction

Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction

January 2023 at a glance: focus on acute heart failure and medical therapy

Clonal hematopoiesis of indeterminate potential: implications for the cardiologists

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