Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1

JAMA Cardiology, Journal Year: 2024, Volume and Issue: 9(6), P. 497 - 497

Published: April 10, 2024

Importance Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk atrial fibrillation (AF) through its association with inflammation and cardiac remodeling. Objective To determine whether CHIP was associated AF, inflammatory biomarkers, structural changes. Design, Setting, Participants This a population-based, prospective cohort study in participants Atherosclerosis Risk Communities (ARIC) UK Biobank (UKB) cohort. Samples were collected echocardiography performed from 2011 2013 ARIC cohort, samples 2006 2010 UKB Included this adults without hematologic malignancies, mitral valve stenosis, or previous procedure both cohorts; additionally, hypertrophic cardiomyopathy congenital heart disease also included. Data analysis completed 2023. Exposures (variant allele frequency [VAF] ≥2%), common gene-specific subtypes ( DNMT3A , TET2 ASXL1 ), large (VAF ≥10%), biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] hs-TnI, N-terminal pro–B-type natriuretic peptide), echocardiographic indices. Main Outcome Measure Incident AF. Results A total 199 982 included study. In (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] 3196 White [77%]), 1019 had any (24.7%), 478 (11.6%). (195 851 [97.9%]; 56 [8] 108 370 [55%]; 87 481 [45%]; 3154 [2%], 183 747 [94%], 7971 other race [4%]), 11 328 (5.8%), 5189 (2.6%). followed up for median (IQR) period 7.0 (5.3-7.7) years, 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios AF 1.12 (95% CI, 1.01-1.25; P = .04) vs CHIP, 1.29 1.05-1.59; .02) those (seen 1340 197 209 [0.67%]), 1.45 1.02-2.07; 314 [0.16%]). Large higher IL-6 levels. Additionally, hs-TnT level increased left ventricular mass index. Conclusions Relevance but not level, indices remodeling, Future research is needed elaborate on mechanisms driving associations investigate interventions reduce risk.

Language: Английский

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Clonal hematopoiesis of indeterminate potential as a prognostic factor: a systematic review and meta-analysis

Blood Advances, Journal Year: 2024, Volume and Issue: 8(14), P. 3771 - 3784

Published: June 5, 2024

With advances in sequencing, individuals with clonal hematopoiesis of indeterminate potential (CHIP) are increasingly being identified, making it essential to understand its prognostic implications. We conducted a systematic review studies comparing the risk clinical outcomes and without CHIP. searched MEDLINE EMBASE included original research reporting an outcome measure CHIP, adjusted for effect age. From 3305 screened, we 88 45 470 960 participants. Most had low-to-moderate bias all domains Quality Prognostic Factor Studies tool. Random-effects meta-analyses were performed reported at least 3 studies. CHIP conferred increased all-cause mortality (hazard ratio [HR], 1.34; 95% confidence interval, 1.19-1.50), cancer (HR, 1.46; 1.13-1.88), composite cardiovascular events 1.40; 1.19-1.65), coronary heart disease 1.76; 1.27-2.44), stroke 1.16; 1.05-1.28), failure 1.27; 1.15-1.41), hematologic malignancy 4.28; 2.29-7.98), lung 1.27-1.54), renal impairment 1.25; 1.18-1.33) severe COVID-19 (odds [OR], 1.18-1.80). was not associated 1.09; 0.97-1.22), except subgroup analysis restricted larger clones 1.31; 1.12-1.54). Isolated DNMT3A mutations did increase myeloid malignancy, mortality, or impairment. The reasons heterogeneity between differences definitions measurements outcomes, populations studied. In summary, is diverse clone size, specific gene, inherent patient characteristics important mediators risk.

Language: Английский

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Invasive Assessment of Coronary Artery Disease in Clonal Hematopoiesis of Indeterminate Potential

Circulation Genomic and Precision Medicine, Journal Year: 2024, Volume and Issue: 17(4)

Published: June 28, 2024

Clonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk atherosclerotic cardiovascular disease. However, there are limited data regarding specific phenotypes. The purpose this study was define the coronary artery disease phenotype population-based on angiography.

Language: Английский

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Clonal hematopoiesis and atherosclerosis

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(19)

Published: Sept. 30, 2024

Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age-related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones mutant cells peripheral blood. The increased developing hematologic malignancy does not, on its own, explain excess mortality individuals with CHIP. Cardiovascular disease accounts much this gap. Experimental evidence supports the causality CHIP accelerated due different varies their promotion atherosclerotic events region augmented involvement. For example, DNMT3a appears less atherogenic than that arises from TET2 or JAK2, forms incite inflammation. recognition promoters opened new insights into understanding pathophysiology disease. accentuated cardiovascular involvement distinct pathways various also inform novel approaches allocation targeted therapies, affording step toward personalized medicine.

Language: Английский

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What Causes Premature Coronary Artery Disease?

Current Atherosclerosis Reports, Journal Year: 2024, Volume and Issue: 26(6), P. 189 - 203

Published: April 4, 2024

Language: Английский

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Clonal Hematopoiesis of Indeterminate Potential in Crohn’s Disease and Ulcerative Colitis

Inflammatory Bowel Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Clonal hematopoiesis of indeterminate potential (CHIP) is the presence somatic mutations in myeloid and lymphoid malignancy genes blood cells individuals without a hematologic malignancy. Inflammation hypothesized to be key mediator progression CHIP patients with have high prevalence inflammatory diseases. This study aimed identify characteristics bowel disease (IBD). We analyzed whole-exome sequencing data from 587 Crohn's (CD), 441 ulcerative colitis (UC), 293 non-IBD controls assess used logistic regression associations clinical outcomes. Older UC (age > 45) harbored increased myeloid-CHIP compared younger ≤ (P = .01). Lymphoid-CHIP was more prevalent older IBD .007). Young CD were found high-risk features. Inflammatory exhibited unique mutational profiles controls. Steroid use associated .05), while anti-TNF therapy decreased .03). Pathway enrichment analyses indicated an overlap between genes, phenotypes, pathways. Our findings underscore connection pathophysiology. Patients had risk profiles, especially among patients. These suggest distinct evolutionary pathways for necessitate awareness providers hematologists potentially at CHIP-related complications including malignancy, cardiovascular disease, acceleration their disease.

Language: Английский

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Clonal Hematopoiesis Associates with Prevalent and Incident Cardiometabolic Disease in High-Risk Individuals

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related presence expanded somatic clones secondary to leukemogenic driver mutations and associated with cardiovascular (CV) disease mortality. We sought evaluate relationships between CHIP cardiometabolic diseases incident outcomes in high-risk individuals. Methods genotyping was performed 8469 individuals referred for cardiac catheterization at Duke University (CATHGEN study) identify variants present a variant allele fraction (VAF) ≥2%. Associations were tested among any variant, large (VAF ≥10%) individual genes prevalent traits. Cox proportional hazard models associations time-to-overall mortality Fine-Gray analyses outcomes. Results identified 463 427 (5.0%) which 268 (3.2%) harbored clones. lower odds obesity (OR 0.79 [95% CI 0.65-0.98], p=0.03; OR 0.76 0.57-0.99], p=0.04, respectively). HF 1.25 1.01 - 1.55], p=0.04; especially non- DNMT3A 1.38 1.04-1.82], p=0.02). also events: Non- increased risk time-to-HF hospitalization (HR 1.29 1.02-1.63], p=0.03). Conclusions In catheterization, DNTM3A obesity, HF, CV events. These findings strengthen importance as biomarker highlight contributing variants. Condensed CHIP, myeloid hematopoietic cells, an emerging CVD biomarker. Using whole exome sequencing peripheral blood derived DNA from participants CATHGEN cohort, we significant mortality, AF after adjusting established clinical factors. add strength growing literature biomarker, emphasizing driving risk. Future studies should aim further elucidate gene-specific inflammatory metabolic mechanisms possibly mediating these relationships. Clinical Perspective What Is New? cohort high prevalence CAD, inversely higher subsequent even adjustment relevant comorbidities. Risk events driven by (VAF≥10%) other than . are Implications? Though more research needed, evidence around specific continues grow, clinicians be prepared provide gene- counseling

Language: Английский

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Clonal hematopoiesis of indeterminate potential and type 2 diabetes mellitus among patients with STEMI: from a prospective cohort study combing bidirectional Mendelian randomization

Cardiovascular Diabetology, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 22, 2025

Both clonal hematopoiesis of indeterminate potential (CHIP) and type 2 diabetes mellitus (T2DM) are conditions closely associated with advancing age. This study delves into the possible implications prognostic significance CHIP T2DM in patients diagnosed ST-segment elevation myocardial infarction (STEMI). Deep-targeted sequencing employing a unique molecular identifier (UMI) for analysis 42 mutations—achieving an impressive mean depth coverage at 1000 × —was conducted on cohort 1430 acute (473 930 non-DM subjects). Variant allele fraction ≥ 2.0% indicated presence mutations. The association between was evaluated by comparison (i) prevalence mutations among individuals versus those without, (ii) clinical characteristics delineated within diabetic (iii) correlation mortality rates subjects. Furthermore, two-sample bidirectional Mendelian randomization performed using genetic instruments from genome-wide TET2 mutation CH UK Biobank (UKB) (2041 cases,173,918 controls) to investigate causal relationship FinnGen consortium (65,085 cases 335,112 controls), vice versa. Most commonly exhibiting variant were identified 50/473 (10.6%) T2DM, demonstrating greater compared subjects [69/930 (7.4%); P < 0.05] across various age groups. After multivariable adjustment, any 2.03-fold higher DM [adjusted hazard ratio (HR) 2.03; 95% confidence interval (CI) 1.07–3.84, 0.05]. In gene-specific analyses, somatic presented highest (adjusted HR 5.24; CI 2.02–13.61, = 0.001). ASXL1 which displayed striking cardiac death (HR: 3.14; 1.24–7.93; 0.05) consistent associations observed subgroup 4.51; 1.30–15.6; 0.05). (iv) PCSK9 Tet2-CHIP both (correlation 0.1215, 0.011) overall enrolled 0.0578, 0.0382). (v) Bidirectional studies that development increases propensity CHIP. However, does not subsequently accelerate onset T2DM. mutations, particularly TET2, more prevalent without diabetes. these is adverse outcomes, notably increased rates. Moreover, analyses provide supporting evidence TET2-related Central Illustration: (T2DM): as demonstrated prospective Asian (AMI). predictive value marker poor prognosis has been assessed this study. suggest may increase CHIP, findings consortium. mellitus; haematopoiesis potential.

Language: Английский

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Plaque erosion risk and JAK2 V617F variant

European Heart Journal, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Clonal haematopoiesis of indeterminate potential (CHIP) can increase the risk myocardial infarction (MI). Among various CHIP mutations, JAK2 V617F substantially elevated this risk. However, specific associations between and two mechanisms MI, plaque erosion rupture, remain unclear. Case-control studies investigated these associations. A total 728 cases, 919 rupture 804 controls were included from our centre. Digital-drop polymerase chain reaction was performed on individuals to identify presence V617F. Previous experimental work has implicated neutrophils in pathogenesis mutation. Thus, single-cell RNA sequencing both carriers healthy donors seek responsible for associated with participants, 26 (3.57%) patients, 7 (.76%) 3 (.37%) identified as a variant allele frequency (VAF) ≥1%. The among patients exhibited higher platelet counts lower glycated haemoglobin blood lipid levels. Logistic regression analysis, considering or separate revealed that VAF ≥1% showed significant association [odds ratio (OR) 16.246, 95% confidence interval (CI) 4.624-57.080, P < .0001], but not (OR 1.677, CI .379-7.415, = .495). Single-cell RNA-sequencing data indicated displayed augmented expression levels genes gene sets activation, adhesion, migration, granule secretion. linked high erosion, an which enhanced neutrophil activation may contribute.

Language: Английский

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Noninvasive Techniques for Tracking Biological Aging of the Cardiovascular System

JACC. Cardiovascular imaging, Journal Year: 2024, Volume and Issue: 17(5), P. 533 - 551

Published: April 8, 2024

Population aging is one of the most important demographic transformations our time. Increasing "health span"—the proportion life spent in good health—is a global priority. Biological comprises molecular and cellular modifications over many years, which culminate gradual physiological decline across multiple organ systems predispose to age-related illnesses. Cardiovascular disease major cause ill health premature death older people. The rate at biological occurs varies individuals same age influenced by wide range genetic environmental exposures. authors review hallmarks cardiovascular their capture using imaging other noninvasive techniques examine how this information may be used understand trajectories, with aim guiding individual- population-level interventions promote healthy aging.

Language: Английский

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