Journal
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Volume 77, Issue 14, Pages 1747-1759Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2021.02.028
Keywords
aging; CHIP; DNMT3A; heart failure; somatic mutation; TET2
Categories
Funding
- Instituto de Salud Carlos III [PI14/01637, PI17/01742]
- Ministerio de Ciencia e Innovacion [RYC-2016-20026, RTI2018-093554-A-I00]
- Fundacion Seneca de Ciencia y Tecnologia de la Region de Murcia [PI14/19334]
- Instituto de Salud Carlos III (ISCIII)
- Ministerio de Ciencia e Innovacion (MCIN)
- Pro CNIC Foundation
- Severo Ochoa Center of Excellence [SEV-2015-0505]
- 2019 Leonardo Grant for Researchers and Cultural Creators from the BBVA Foundation
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This study found that clonal hematopoiesis mutations are common among HF patients with reduced LVEF and are associated with accelerated HF progression, regardless of whether the etiology is ischemic or nonischemic.
BACKGROUND Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown. METHODS The study cohort comprised 62 patients with HF and LVEF <45% (age 74 +/- 7 years, 74% men, 52% nonischemic, and LVEF 30 +/- 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization. RESULTS CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology. CONCLUSIONS Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology. (J Am Coll Cardiol 2021;77:1747-59) (c) 2021 Published by Elsevier on behalf of the American College of Cardiology Foundation.
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