Clonal Hematopoiesis has Prognostic Value in Dilated Cardiomyopathy independent of Age and Clone Size

BACKGROUND: Clonal hematopoiesis (CH) gives rise to mutated leukocyte clones that induce cardiovascular inflammation, and thereby impact the disease course in atherosclerosis and ischemic heart failure. Clonal hematopoiesis of indeterminate potential (CHIP) refers to a variant allele frequency (VAF; a marker for clone size) in blood of =2%. The impact of CH clones -including small clone sizes (VAF<0.5%)- in non-ischemic dilated cardiomyopathy (DCM) remains largely undetermined. OBJECTIVES: To establish the prognostic impact of CH in DCM including small clones. METHODS: CH is 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 analyzed using receiver operating characteristic curve-optimized VAF cut-off values. RESULTS: Five hundred twenty DCM patients have been included. One hundred and nine patients (21%) had CH driver mutations, of which 45 had a VAF of =2% and 31 <0.5%. The median follow-up duration is 6.5 years [interquartile range 4.7-9.7]. DCM patients with CH have 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 is prognostically relevant independent of clone size in patients with DCM.