Causes and consequences of clonal hematopoiesis

Blood, Год журнала: 2023, Номер 142(26), С. 2235 - 2246

Опубликована: Ноя. 6, 2023

Abstract Clonal hematopoiesis (CH) is described as the outsized contribution of expanded clones hematopoietic stem and progenitor cells (HSPCs) to blood cell production. The prevalence CH increases dramatically with age. can be caused by somatic mutations in individual genes or gains and/or losses larger chromosomal segments. a premalignant state; detected are initiating for hematologic malignancies, strong predictor development cancers. Moreover, associated nonmalignant disorders increased overall mortality. that drive clonal expansion HSPCs alter function terminally differentiated cells, including release elevated levels inflammatory cytokines. These cytokines may then contribute broad range increase Specific peripheral coordination count parameters powerfully predict malignancies mortality CH. In this review, we summarize current understanding nosology origins. We provide an overview available tools risk stratification discuss management strategies patients presenting hematology clinics.

Язык: Английский

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Somatic and Germline Variants and Coronary Heart Disease in a Chinese Population

JAMA Cardiology, Год журнала: 2024, Номер 9(3), С. 233 - 233

Опубликована: Янв. 10, 2024

The genetic basis of coronary heart disease (CHD) has expanded from a germline to somatic genome, including clonal hematopoiesis indeterminate potential (CHIP). How CHIP confers CHD risk in East Asian individuals, especially those with small clones (variant allele fraction [VAF] 0.5%-2%) and different backgrounds, was completely unknown.

Язык: Английский

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Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

JAMA Network Open, Год журнала: 2024, Номер 7(1), С. e2353244 - e2353244

Опубликована: Янв. 25, 2024

Importance Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion hematopoietic stem cells with leukemogenic acquired genetic variants, is associated incident heart failure (HF). Objective To evaluate associations CHIP and key gene-specific subtypes HF preserved ejection fraction (HFpEF) reduced (HFrEF). Design, Setting, Participants This population-based cohort study included participants from 2 racially diverse prospective studies uniform subtype adjudication: Jackson Heart Study (JHS) Women’s Health Initiative (WHI). JHS were enrolled during 2000 to 2004 followed up through 2016. WHI 1993 1998 2022. who underwent whole-genome sequencing, lacked prevalent at baseline, for adjudication included. Follow-up occurred over a median (IQR) 12.0 (11.0-12.0) years in 15.3 (9.0-22.0) WHI. Statistical analysis was performed June December 2023. Exposures Any most common ( DNMT3A TET2 CHIP). Main Outcomes Measures First hospitalized events adjudicated hospital records classified as HFpEF (left ventricular ≥50%) or HFrEF (ejection <50%). Results A total 8090 included; 2927 (median [IQR] age, 56 [46-65] years; 1846 [63.1%] female; [100.0%] Black African American) 5163 67 [62-72] 29 [0.6%] American Indian Alaska Native, 37 [0.7%] Asian Pacific Islander, 1383 [26.8%] American, 293 [5.7%] Hispanic Latinx, 3407 [66.0%] non-Hispanic White, 14 [0.3%] other race ethnicity). The multivariable-adjusted hazard ratio (HR) composite 1.28 (95% CI, 0.93-1.76; P = .13), it 0.79 0.49-1.25; .31). both cohorts (meta-analyzed HR, 2.35 [95% 1.34 4.11]; .003) independent cardiovascular risk factors coronary artery disease. Analyses stratified by C-reactive protein (CRP) found an increased individuals CRP greater than equal mg/L (HR, 1.94 1.20-3.15]; .007), but not those less without CHIP, when compared mg/L. Conclusions Relevance In this study, factor HFpEF. finding may have implications prevention management HFpEF, including development targeted therapies.

Язык: Английский

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Genetic variation across and within individuals

Nature Reviews Genetics, Год журнала: 2024, Номер 25(8), С. 548 - 562

Опубликована: Март 28, 2024

Язык: Английский

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Atherosclerotic burden and cerebral small vessel disease: exploring the link through microvascular aging and cerebral microhemorrhages

GeroScience, Год журнала: 2024, Номер 46(5), С. 5103 - 5132

Опубликована: Апрель 19, 2024

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They prevalent in the aging population, with multiple often being observed given individual. closely associated accelerated cognitive decline and increasingly recognized key contributors to pathogenesis vascular impairment dementia (VCID) Alzheimer's (AD). This review paper delves into hypothesis that atherosclerosis, age-related large disease, extends its influence microcirculation, thereby contributing development progression CSVD, specific focus on CMHs. We explore concept continuum, bridging macrovascular pathologies like atherosclerosis microvascular abnormalities characteristic CSVD. posit same risk factors precipitating vessels (i.e., atherogenesis), primarily oxidative stress inflammatory pathways, similarly instigate aging. Accelerated leads increased fragility, which turn predisposes formation The presence hypertension amyloid pathology further intensifies this process. comprehensively overview current body evidence supporting interconnected hypothesis. Our includes examination epidemiological data, provides insights prevalence impact context Furthermore, we shared mechanisms between aging, atherogenesis, particularly focusing how these intertwined processes contribute genesis By highlighting role pathophysiology CMHs, seeks enhance understanding CSVD links systemic disorders. aim is provide could inform future therapeutic approaches research directions realm neurovascular health.

Язык: Английский

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Colchicine prevents accelerated atherosclerosis in TET2-mutant clonal haematopoiesis

European Heart Journal, Год журнала: 2024, Номер unknown

Опубликована: Авг. 30, 2024

Somatic mutations in the TET2 gene that lead to clonal haematopoiesis (CH) are associated with accelerated atherosclerosis development mice and a higher risk of atherosclerotic disease humans. Mechanistically, these observations have been linked exacerbated vascular inflammation. This study aimed evaluate whether colchicine, widely available inexpensive anti-inflammatory drug, prevents TET2-mutant CH.

Язык: Английский

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Clonal Hematopoiesis Is Associated With Adverse Clinical Outcomes and Left Ventricular Remodeling in Aortic Stenosis

JACC Advances, Год журнала: 2025, Номер 4(2), С. 101532 - 101532

Опубликована: Янв. 8, 2025

Clonal hematopoiesis of indeterminate potential (CHIP) has been linked to intensified systemic inflammation and represents a novel risk factor for atherosclerotic cardiovascular diseases, including aortic stenosis (AS). This study aimed assess the clinical impact CHIP in cohort severe AS patients undergoing transcatheter valve implantation (TAVI). We enrolled 110 this retrospective study. Targeted next-generation sequencing was employed detect somatic mutations with variant allele frequency >2% 16 genes most frequently associated CHIP. Correlative analyses on clinical, laboratory, echocardiographic parameters were also performed. The primary endpoint post-TAVI heart failure hospitalization. Multivariate Cox regression model used account confounding effects relevant factors. detected 40 (36.4%) our cohort. commonly mutated DNMT3A, TET2, ASXL1. With median follow-up 55.2 months, carrying had significantly higher hospitalization rate (adjusted HR: 3.060; 95% CI: 1.090-8.589; P = 0.034) than those without Additionally, harboring serum ferritin levels, as well evidence left ventricular hypertrophy diastolic dysfunction. Our supports adverse TAVI, which could be attributed maladaptive LV remodeling. Prospective trials are anticipated validate findings provide further that holds being an actionable therapeutic target AS.

Язык: Английский

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Association of clonal haematopoiesis with heart failure incidence and outcomes: A systematic review and meta‐analysis

European Journal of Heart Failure, Год журнала: 2025, Номер unknown

Опубликована: Март 10, 2025

Clonal haematopoiesis (CH) is recognized as a significant risk factor for various non-haematologic conditions, including cardiovascular diseases. However, recent studies examining its relationship with heart failure (HF) have reported conflicting findings. To address these inconsistencies, the present meta-analysis aimed to evaluate association of CH incidence and clinical outcomes HF. MEDLINE, Cochrane Library Scopus were searched until 12 December 2024. Triple-independent study selection, data extraction quality assessment performed. Evidence was pooled using three-level mixed-effects meta-analyses. Participants (n = 57 755) had significantly greater new-onset HF compared non-CH group (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.12-1.35, p < 0.0001; I2 0%), irrespective prior history coronary artery disease. also correlated higher composite outcome all-cause mortality hospitalization (HHF) in patients established (HR 1.84, CI 1.25-2.70, 0.002; 0%). Specifically, associated 1.95, 1.54-2.47, 3% increase every 1% variant allele fraction. concomitant 56% HHF 1.56, 1.05-2.33, 0.029; 19%). an increased incident worse prognosis individuals affected by These findings highlight potential contribute deeper understanding HF, improve stratification, support more personalized approaches management.

Язык: Английский

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Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias

European Heart Journal, Год журнала: 2023, Номер 45(10), С. 791 - 805

Опубликована: Ноя. 11, 2023

Abstract Background and Aims Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion blood cells with preleukemic mutations, is associated atherosclerotic cardiovascular disease heart failure. This study aimed to test association CHIP new-onset arrhythmias. Methods UK Biobank participants without prevalent arrhythmias were included. Co-primary outcomes supraventricular arrhythmias, bradyarrhythmias, ventricular Secondary cardiac arrest, atrial fibrillation, any arrhythmia. Associations [variant allele fraction (VAF) ≥ 2%], large (VAF ≥10%), gene-specific subtypes incident evaluated using multivariable-adjusted Cox regression. myocardial interstitial fibrosis [T1 measured magnetic resonance (CMR)] also tested. Results included 410 702 [CHIP: n = 13 892 (3.4%); CHIP: 9191 (2.2%)]. Any multi-variable-adjusted hazard ratios 1.11 [95% confidence interval (CI) 1.04–1.18; P .001] 1.13 (95% CI 1.05–1.22; .001) for 1.09 1.01–1.19; .031) 1.03–1.25; .011) 1.16 CI, 1.00–1.34; .049) 1.22 1.03–1.45; .021) respectively. independent coronary artery heterogeneous across arrhythmia strongest arrest. Gene-specific analyses revealed an increased risk driver genes other than DNMT3A. Large was 1.31-fold odds 1.07–1.59; .009) being in top quintile by CMR. Conclusions may represent a novel factor indicating target modulation towards prevention treatment.

Язык: Английский

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Inflammation and the pathogenesis of atherosclerosis

Vascular Pharmacology, Год журнала: 2023, Номер 154, С. 107255 - 107255

Опубликована: Дек. 28, 2023

Язык: Английский

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