Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

JAMA Network Open, Journal Year: 2024, Volume and Issue: 7(1), P. e2353244 - e2353244

Published: Jan. 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.

Language: Английский

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Unidirectional association of clonal hematopoiesis with atherosclerosis development

Nature Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

Clonal hematopoiesis, a condition in which acquired somatic mutations hematopoietic stem cells lead to the outgrowth of mutant clone, is associated with higher risk hematological cancer and growing list nonhematological disorders, most notably atherosclerosis cardiovascular disease. However, whether accelerated cause or consequence clonal hematopoiesis remains matter debate. Some studies support direct contribution certain hematopoiesis-related via exacerbation inflammatory responses, whereas others suggest that symptom rather than atherosclerosis, as related traits may accelerate expansion clones. Here we combine high-sensitivity DNA sequencing blood noninvasive vascular imaging investigate interplay between longitudinal cohort healthy middle-aged individuals. We found presence mutation confers an increased developing de novo femoral over 6-year period, neither nor extent affects cell during this timeframe. These findings indicate unidirectionally promotes should help translate understanding into strategies for prevention atherosclerotic disease individuals exhibiting hematopoiesis.

Language: 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, Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

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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Malignant JAK-signaling: at the interface of inflammation and malignant transformation

Leukemia, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Abstract The JAK pathway is central to mammalian cell communication, characterized by rapid responses, receptor versatility, and fine-tuned regulation. It involves Janus kinases (JAK1, JAK2, JAK3, TYK2), which are activated when natural ligands bind receptors, leading autophosphorylation activation of STAT transcription factors [1, 2]. JAK-dependent signaling plays a pivotal role in coordinating communication networks across broad spectrum biological systems including development, immune growth, differentiation. JAKs frequently mutated the aging hematopoietic system [3, 4] cancers [5]. Thus, dysregulation results various diseases, disorders. binding extracellular class I II cytokine receptors initiates critical cascade through (JAKs). Upon ligand engagement, become phosphorylate specific tyrosine residues on receptor, creating docking sites for signal transducer activator (STAT) proteins. Subsequent JAK-mediated phosphorylation STATs enables their dimerization nuclear translocation, where they function as modulate gene expression. Under physiological conditions, JAK-signaling tightly regulated mechanism that governs cellular responses external cues, such cytokines growth factors, ensuring homeostasis maintaining functional integrity tissues organs. Highly defined regulation essential balancing inflammatory stimuli signals, thus safeguarding tissue health. In contrast, dysregulated chronic inflammation unrestrained proliferation associated with diseases. Understanding qualitative quantitative differences at interface physiologic its aberrant disease crucial development targeted therapies precisely tune this target pathologic patterns while leaving homeostatic processes largely unaffected. Consequently, pharmaceutical research has drug approval several substances different selectivity profiles towards individual JAKs. Yet, precise impact inhibitor complex interplay modules within normal malignant cells remains incompletely understood. review, we summarize current knowledge health highlight recent advances future directions field.

Language: Английский

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Genetic Factors Altering Immune Responses in Atrial Fibrillation

Journal of the American College of Cardiology, Journal Year: 2024, Volume and Issue: 83(12), P. 1163 - 1176

Published: March 1, 2024

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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Non-traditional risk factors for atrial fibrillation: epidemiology, mechanisms, and strategies

European Heart Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 24, 2024

Atrial fibrillation (AF) has become the pre-dominant arrhythmia worldwide and is associated with high morbidity mortality. Its pathogenesis intricately linked to deleterious impact of cardiovascular risk factors, emphasizing pivotal imperative for early detection mitigation strategies targeting these factors prevention primary AF. While traditional are well recognized, an increasing number novel have been identified in recent decades. This review explores emerging non-traditional AF, including unhealthy lifestyle current society (sleep, night shift work, diet), biomarkers (gut microbiota, hyperuricaemia, homocysteine), adverse conditions or diseases (depression, epilepsy, clonal haematopoiesis indeterminate potential, infections, asthma), environmental (acoustic pollution other factors). Unlike individuals limited control over many posing challenges conventional strategies. The purpose this outline evidence on associations new-onset AF potential mechanisms related factors. Furthermore, aims explore interventions at both individual societal levels mitigate growing burden suggesting guideline updates prevention.

Language: Английский

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Natural history of clonal haematopoiesis seen in real‐world haematology settings

British Journal of Haematology, Journal Year: 2024, Volume and Issue: 204(5), P. 1844 - 1855

Published: March 24, 2024

Summary Recursive partitioning of healthy consortia led to the development Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in practical setting, most cases CH are diagnosed after patients present with cytopenias or related symptoms. To address this real‐world population, we characterize clinical trajectories 94 and distinguish harbouring canonical DNMT3A/TET2/ASXL1 mutations alone (‘sole DTA’) versus all other groups (‘non‐sole DTA’). TET2 , rather than DNMT3A was prevalent mutation setting. Sole DTA did not progress myeloid neoplasm (MN) absence acquisition mutations. Contrastingly, 14 (20.1%) 67 non‐sole progressed MN. CHRS assessment showed a higher frequency high‐risk (vs. sole DTA) progressors non‐progressors). RUNX1 conferred strongest risk progression MN (odds ratio [OR] 10.27, 95% CI 2.00–52.69, p = 0.0053). The mean variant allele across genes non‐progressors (36.9% ± 4.62% vs. 24.1% 1.67%, 0.0064). This analysis post‐CHRS era underscores natural history CH, providing insight into patterns

Language: Английский

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Clinical and Therapeutic Implications of Clonal Hematopoiesis

Annual Review of Genomics and Human Genetics, Journal Year: 2024, Volume and Issue: 25(1), P. 329 - 351

Published: Aug. 27, 2024

Clonal hematopoiesis (CH) is an age-related process whereby hematopoietic stem and progenitor cells (HSPCs) acquire mutations that lead to a proliferative advantage clonal expansion. The most commonly mutated genes are epigenetic regulators, DNA damage response genes, splicing factors, which essential maintain functional HSPCs frequently involved in the development of hematologic malignancies. Established risk factors for CH, including age, prior cytotoxic therapy, smoking, increase acquiring CH and/or may fitness. has emerged as novel factor many diseases, such malignancies, cardiovascular disease, diabetes, autoimmune disorders, among others. Future characterization mechanisms driving evolution will be critical develop preventative therapeutic approaches.

Language: Английский

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