Publication: Clonal haematopoiesis of indeterminate potential: associations with heart failure incidence, clinical parameters and biomarkers

Clonal hematopoiesis of indeterminate potential (CHIP) describes a clonal expansion of hematopoietic cells with hematologic malignancy-associated somatic mutations, in the absence of a hematological malignancy. Among all mutations, DNMT3A, TET2 and ASXL1 are three predominant CHIP driver genes, involved in the epigenetic regulation of inflammation.

CHIP has been the focus of a number of studies. The prevalence of CHIP increases with age, and associates with hematological cancer and mortality. Interestingly, it has been demonstrated that CHIP also increases the risks of incident coronary heart disease, myocardial infarction and stroke. As such, CHIP has been positioned as a link between cancer and cardiovascular disease, and is considered to be a potential common genetic risk factor in the cardio-oncology field.

Recent clinical data have shown that in patients with chronic heart failure (HF), CHIP is significantly associated with all-cause mortality and HF hospitalization, best characterized by DNMT3A and TET2 mutations. Similar associations were reported among HF patients with reduced ejection fraction (HFrEF). Moreover, a large American cohort study including over 50 000 participants found that CHIP correlated with a 25% increased risk of new-onset HF.

However, the effects of CHIP mutations on HF risk factors and biomarkers, and HF incidence among the European population, and whether the effects vary between HF phenotypes remain unexplored. On this basis, the authors designed a case–control study to assess the associations of CHIP mutations with incident HF and HF subtypes (heart failure with preserved ejection fraction [HFpEF] and HFrEF) in the Prevention of Renal and Vascular End-stage Disease [PREVEND] cohort.

The authors included all 374 participants with incident HF and selected 1:1 age- and sex-matched control subjects. Peripheral blood samples of 705 individuals were successfully analyzed by error-corrected next generation sequencing for acquired mutations at a variant allele frequency ≥2% in 27 CHIP driver genes.

The median age of the study population was 65 years (interquartile range 58–70) and 35.6% were female. CHIP mutations positively correlated with age, smoking, hypertension and cardiovascular biomarkers including N-terminal pro-B-type natriuretic peptide and mid-regional pro-A-type natriuretic peptide, but the frequency of CHIP was comparable in individuals with incident HF and in control participants (18.4% vs. 17.3%; p = 0.69).

In multivariable Cox regression models, CHIP was not significantly associated with incident HF (hazard ratio [HR] 1.24, 95% confidence interval [CI] 0.93–1.65; p = 0.144). This association, however, was modified by age (p for CHIP–age interaction = 0.002). Among people younger than 65 years, CHIP mutations were more frequently detected in the case cohort compared to the control cohort (14.2% vs. 5.8%; p = 0.009), and were significantly associated with new-onset HF (HR 2.07, 95% CI 1.30–3.29; p = 0.002).

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Key message:

CHIP correlates with HF risk factors and biomarkers, and is associated with incident HF in subjects <65 years of age in PREVEND cohort.