Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study

European Heart Journal, Journal Year: 2024, Volume and Issue: 45(10), P. 778 - 790

Published: Jan. 17, 2024

Abstract Background and Aims Both clonal haematopoiesis of indeterminate potential (CHIP) atrial fibrillation (AF) are age-related conditions. This study investigated the role CHIP in development progression AF. Methods Deep-targeted sequencing 24 mutations (a mean depth coverage = 1000×) was performed 1004 patients with AF 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated presence mutations. The association between evaluated by comparison (i) prevalence subjects (ii) clinical characteristics discriminated within patients. Furthermore, risk outcomes—the composite heart failure, ischaemic stroke, or death—according to from UK Biobank cohort. Results age 67.6 ± 6.9 vs. 58.5 6.5 years (paroxysmal, 39.0%; persistent, 61.0%) cohorts, respectively. a variant ≥2.0% were found 237 (23.6%) (DNMT3A, 13.5%; TET2, 6.6%; ASXL1, 1.5%) more prevalent than [356 (10.7%); P < .001] across age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, hypertension), 1.4-fold higher [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10–1.74, .01]. ORs highest long-standing persistent (adjusted OR 1.50; 1.14–1.99, .004) followed 1.44) paroxysmal 1.33) In gene-specific analyses, TET2 somatic mutation presented 1.65; 1.05–2.60, .030). older had longer duration, E/E′, severely enlarged left atrium those without (all .05). analysis 21 286 (1297 19 989 CHIP), is associated 1.32-fold event (heart death). Conclusions mutations, primarily DNMT3A whilst their progressive nature unfavourable outcomes.

Language: Английский

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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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Caloric restriction and its mimetics in heart failure with preserved ejection fraction: mechanisms and therapeutic potential

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

Published: Jan. 18, 2025

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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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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Deep learning of left atrial structure and function provides link to atrial fibrillation risk

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 21, 2024

Abstract Increased left atrial volume and decreased function have long been associated with fibrillation. The availability of large-scale cardiac magnetic resonance imaging data paired genetic provides a unique opportunity to assess the contributions structure function, understand their relationship risk for Here, we use deep learning surface reconstruction models measure minimum volume, maximum stroke emptying fraction in 40,558 UK Biobank participants. In genome-wide association study 35,049 participants without pre-existing cardiovascular disease, identify 20 common loci function. We find that polygenic increased are fibrillation its downstream consequences, including stroke. Through Mendelian randomization, evidence supporting causal role enlargement dysfunction on risk.

Language: Английский

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Experimental TET2 Clonal Hematopoiesis Predisposes to Renal Hypertension Through an Inflammasome-Mediated Mechanism

Circulation Research, Journal Year: 2024, Volume and Issue: 135(9), P. 933 - 950

Published: Sept. 5, 2024

BACKGROUND: Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease. Clonal events in hematopoietic system resulting from somatic mutations driver genes are elderly individuals who lack overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (CH), it a newly recognized factor It not known whether CH hypertension causally related and, if so, what mechanistic features. METHODS: A murine model adoptive bone marrow transplantation was employed examine interplay between Tet2 (ten-eleven translocation methylcytosine dioxygenase 2) hypertension. RESULTS: In this model, subpressor dose Ang II (angiotensin II) resulted elevated systolic diastolic blood pressure early 1 day after challenge. These conditions led expansion Tet2-deficient proinflammatory monocytes progenitor populations. deficiency promoted renal CCL5 (C-C motif ligand 5) chemokine expression macrophage infiltration into kidney. Consistent involvement, myeloid cells when mice were treated II. The −/− sodium retention, inflammasome activation, levels IL (interleukin)-1β IL-18. Analysis transporters indicated NCC (sodium-chloride symporter) NKCC2 (Na + -K -Cl − cotransporter activation at residues Thr53 Ser105, respectively. Administration NLRP3 (NLR family pyrin domain containing 3) inhibitor MCC950 reversed hypertensive state, transporter activation. CONCLUSIONS: Tet2-mediated sensitizes stimulus. Mechanistically, promotes due immune cell inflammasome, consequences on retention. data indicate that carriers TET2 could be development modulators useful treating patient population.

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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Clonal hematopoiesis, cardiovascular disease and cancer treatment-induced cardiotoxicity

Seminars in Cancer Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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