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Clonal Hematopoiesis Has Prognostic Value in Dilated Cardiomyopathy Independent of Age and Clone Size
Maurits A Sikking1, Sophie L V M Stroeks2, Michiel T H M Henkens3
1Department of Cardiology, Maastricht University Medical Center, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands.
Insights
Clonal hematopoiesis (CH) predicts cardiac death and all-cause mortality in dilated cardiomyopathy (DCM) patients. This impact is significant even for small CH clones, independent of their size.
Area of Science:
- Cardiology
- Genetics
- Oncology
Background:
- Clonal hematopoiesis (CH) involves mutated leukocyte clones contributing to cardiovascular inflammation, impacting atherosclerosis and ischemic heart failure.
- CH of indeterminate potential is defined by a variant allele frequency (VAF) ≥2% in blood.
- The prognostic significance of CH, particularly small clones (VAF <0.5%), in nonischemic dilated cardiomyopathy (DCM) is not well understood.
Purpose of the Study:
- To determine the prognostic impact of clonal hematopoiesis (CH) in patients with dilated cardiomyopathy (DCM).
- To investigate the role of CH, including small clones, in predicting adverse outcomes in DCM.
- To establish optimal variant allele frequency (VAF) thresholds for CH detection in DCM.
Main Methods:
- Utilized an ultrasensitive single-molecule molecular inversion probe technique for CH detection, enabling identification of clones with VAF as low as 0.01%.
- Analyzed cardiac death and all-cause mortality in 520 DCM patients.
- Employed receiver-operating characteristic curve-optimized VAF cutoff values to assess prognostic significance.
Main Results:
- Identified CH driver mutations in 109 out of 520 (21%) DCM patients.
- Observed a significantly higher risk of cardiac death (HR: 2.33, VAF cutoff 0.36%) and all-cause mortality (HR: 1.72, VAF cutoff 0.06%) in DCM patients with CH.
- CH-associated mortality risk was independent of established prognostic factors like age, sex, LVEF, and NYHA class.
Conclusions:
- Clonal hematopoiesis (CH) serves as a significant predictor of cardiac death and all-cause mortality in patients with dilated cardiomyopathy (DCM).
- Optimal VAF thresholds for CH detection in DCM were identified as 0.36% for cardiac death and 0.06% for all-cause mortality.
- CH is prognostically relevant in DCM, irrespective of the identified 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. CH of indeterminate potential 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 nonischemic dilated cardiomyopathy (DCM) remains largely undetermined.
Objectives:
The authors sought 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 cutoff values.
Results:
A total of 520 DCM patients have been included. A total of 109 patients (21%) had CH driver mutations, of which 45 had a VAF of ≥2% and 31 <0.5%. The median follow-up duration was 6.5 years (IQR: 4.7-9.7 years). DCM patients with CH have a higher risk of cardiac death (HR: 2.33 using a VAF cutoff of 0.36%, 95% CI: 1.24-4.40) and all-cause mortality (HR: 1.72 using a VAF cutoff of 0.06%, 95% CI: 1.10-2.69), independent of age, sex, left ventricular ejection fraction, and NYHA functional classification.
Conclusions:
CH predicts cardiac death and all-cause mortality in DCM patients with optimal thresholds for clone size of 0.36% and 0.06%, respectively. Therefore, CH is prognostically relevant, independent of clone size in patients with DCM.
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