Domingo A Pascual-Figal1, Antoni Bayes-Genis2, Miriam Díez-Díez3, Álvaro Hernández-Vicente4, David Vázquez-Andrés4, Jorge de la Barrera3, Enrique Vazquez3, Ana Quintas3, María A Zuriaga3, Mari C Asensio-López4, Ana Dopazo3, Fátima Sánchez-Cabo3, José J Fuster5. 1. Cardiology Department, Hospital Virgen de la Arrixaca, IMIB-Arrixaca and University of Murcia, Murcia, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, (CIBERCV), Madrid, Spain. Electronic address: dpascual@um.es. 2. Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, (CIBERCV), Madrid, Spain; Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 3. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. 4. Cardiology Department, Hospital Virgen de la Arrixaca, IMIB-Arrixaca and University of Murcia, Murcia, Spain. 5. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address: jjfuster@cnic.es.
Abstract
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. OBJECTIVES: The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology. 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.
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. OBJECTIVES: The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology. 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.
Authors: Luca Liberale; Lina Badimon; Fabrizio Montecucco; Thomas F Lüscher; Peter Libby; Giovanni G Camici Journal: J Am Coll Cardiol Date: 2022-03-01 Impact factor: 24.094
Authors: Caitlyn Vlasschaert; Amy J M McNaughton; Michael Chong; Elina K Cook; Wilma Hopman; Bryan Kestenbaum; Cassianne Robinson-Cohen; Jocelyn Garland; Sarah M Moran; Guillaume Paré; Catherine M Clase; Mila Tang; Adeera Levin; Rachel Holden; Michael J Rauh; Matthew B Lanktree Journal: J Am Soc Nephrol Date: 2022-02-23 Impact factor: 14.978