Clonal hematopoiesis has prognostic value in dilated cardiomyopathy independent of age and clone size

Abstract

Abstract Background Clonal hematopoiesis (CH) gives rise to mutated leukocyte clones, that may induce cardiovascular inflammation, and thereby impact the disease course in cardiovascular diseases such as atherosclerosis and ischemic heart failure. The term clonal hematopoiesis of indeterminate potential (CHIP) is used when the variant allele frequency (VAF; a marker for clone size) in blood is ≥2%. The impact of CH clones in non-ischemic dilated cardiomyopathy (DCM) remains largely undetermined. Moreover, the impact of small clone sizes (VAF <0.5%) remains unknown in cardiovascular diseases in general. Objectives To establish the prognostic impact of CH in DCM down to small CH clone sizes. Methods CH was determined using an ultrasensitive single-molecule Molecular Inversion Probe technique that allows detection of clones down to a VAF of 0.01%. Cardiac death and all-cause mortality were predicted using receiver operating characteristic curve-optimized VAF cut-off values. Results 520 DCM patients were included. 109 patients (21%) had CH driver mutations, of which 45 had a VAF of ≥2% and 31 had a VAF of <0.5%. The median follow-up duration was 6.49 years [interquartile range 4.69 - 9.71]. DCM patients with CH had a higher risk of cardiac death (HR 2.33 using a VAF cut-off of 0.36%, 95% confidence interval 1.24 - 4.40) and all-cause mortality(HR 1.72 using a VAF cut-off of 0.06%, 95% confidence interval 1.10 - 2.69), independent of age, sex, left ventricle ejection fraction and New York Heart Association classification. Conclusion CH predicts cardiac death and all-cause mortality in DCM patients with an optimal threshold for clone size of 0.36% and 0.06%, respectively. Therefore, CH may be prognostically relevant independent of clone size in patients with DCM.Clonal hematopoiesis characteristicsClonal hematopoiesis prognosis