Full spectrum of clonal haematopoiesis‐driver mutations in chronic heart failure and their associations with mortality

Abstract

Aims Somatic mutations in haematopoietic stem cells can lead to the clonal expansion of mutated blood cells, known as clonal haematopoiesis (CH). Mutations in the most prevalent driver genes DNMT3A and TET2 with a variant allele frequency (VAF) ≥ 2% have been associated with atherosclerosis and chronic heart failure of ischemic origin (CHF). However, the effects of mutations in other driver genes for CH with low VAF (<2%) on CHF are still unknown. Methods and results Therefore, we analysed mononuclear bone marrow and blood cells from 399 CHF patients by deep error-corrected targeted sequencing of 56 genes and associated mutations with the long-term mortality in these patients (3.95 years median follow-up). We detected 1113 mutations with a VAF ≥ 0.5% in 347 of 399 patients, and only 13% had no detectable CH. Despite a high prevalence of mutations in the most frequently mutated genes DNMT3A (165 patients) and TET2 (107 patients), mutations in CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A, and SRSF2 were associated with increased death compared with the average death rate of all patients. To avoid confounding effects, we excluded patients with DNMT3A-related, TET2-related, and other clonal haematopoiesis of indeterminate potential (CHIP)-related mutations with a VAF ≥ 2% for further analyses. Kaplan-Meier survival analyses revealed a significantly higher mortality in patients with mutations in either of the seven genes (53 patients), combined as the CH-risk gene set for CHF. Baseline patient characteristics showed no significant differences in any parameter including patient age, confounding diseases, severity of CHF, or blood cell parameters except for a reduced number of platelets in patients with mutations in the risk gene set in comparison with patients without. However, carrying a mutation in any of the risk genes remained significant after multivariate cox regression analysis (hazard ratio, 3.1; 95% confidence interval, 1.8-5.4; P < 0.001), whereas platelet numbers did not. Conclusions Somatic mutations with low VAF in a distinct set of genes, namely, in CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A, and SRSF2, are significantly associated with mortality in CHF, independently of the most prevalent CHIP-mutations in DNMT3A and TET2. Mutations in these genes are prevalent in young CHF patients and comprise an independent risk factor for the outcome of CHF, potentially providing a novel tool for risk assessment in CHF.

Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study

“…These findings are in line with previously published data. 7,49 Multiple studies indicate an increased cardiovascular risk in CHIP 11,[15][16][17][18][19][20][21] , presumably via increased microinflammation. Marked glomerulosclerosis and increased kidney fibrosis when challenged with angiotensin II were described in mouse models representing a setting with TET2 and DNMT3A variants 15,22 .…”

“…[11][12][13] As somatic variants accumulate in different cell types throughout life 14 , the prevalence of CHIP increases considerably with advancing age. [11][12][13] In previous studies the presence of CHIP has been associated with increased risk of coronary heart disease, ischemic stroke and heart failure 11,[15][16][17] as well as adverse outcomes in patients with heart failure [18][19][20] or degenerative aortic valve stenosis. 21 Experimental data suggest endothelial as well as tissue inflammation and fibrosis via clonally-derived macrophages and monocytes as possible mechanisms behind adverse outcomes.…”

Cardiovascular Disease in Myeloproliferative Neoplasms

“…Other studies have shown that patients with heart failure who have CHIP mutations (particularly in DNMT3a or TET2 ) have worse outcomes compared with those without CHIP. 16 , 17 , 18 Moreover, patients who have undergone percutaneous aortic valve replacement also fare much more poorly if they carry DNMT3a or TET2 mutations. 19 These recent discoveries suggest elements of shared pathogenesis that connect disorders of clonal hematopoiesis, including MPNs, to atherosclerosis and cardiovascular events.…”

Einfluss der klonalen Hämatopoese auf nicht-hämatologische Erkrankungen und Alterungsprozesse

“…Mehr als 10 % aller 60-Jährigen haben einen mutierten CHIP-Klon, und die Häufigkeit steigt rapide mit zunehmendem Alter. Bemerkenswert ist, dass ein deutlich höherer Anteil bereits in jüngeren Jahren kleine, mutierte Blutzellklone trägt [ 4 , 5 ].…”

“…Bei Patient*innen mit Herzinsuffizienz spielen offensichtlich bereits kleine mutierte Blutzellklone eine entscheidende Rolle. Außer DNMT3A und TET2 konnten weitere Risikogene für Herzinsuffizienz gefunden werden, die auch zu klonaler Hämatopoese führen [ 4 , 16 ]. Ultratiefe DNA-Sequenzierung in Blutzellen ermöglichte die akkurate Quantifizierung von Genmutationen mit einer VAF > 0,5 % – weit unter der CHIP-Definitionsgrenze von VAF > 2 % – und zeigte ein Spektrum der Mutationslandschaft in CHIP-Treibergenen bei Patient*innen mit Herzinsuffizienz [ 4 , 16 ].…”