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What is the clinical significance of clonal hematopoiesis of indeterminate potential (CHIP) for chronic heart failure (CHF) owing to ischemic origin?
In this cohort study, CHIP had a high prevalence in 200 investigated patients with CHF. While no clinical baseline characteristics associated with CHF were different between CHIP carriers and non-CHIP carriers, except for the mean age, harboring mutations in the most prevalent driver genes associated with CHIP, namely DNMT3A and TET2, was associated with a significant and profound increase in death and rehospitalization for heart failure.
Clonal hematopoiesis of indeterminate potential is presented as a newly identified risk factor for impaired long-term survival and increased disease progression in patients with CHF that may be well targetable as a valuable approach to precision medicine in patients with CHF carrying specific mutations encoding for clonal hematopoiesis.
Somatic mutations causing clonal expansion of hematopoietic cells (clonal hematopoiesis of indeterminate potential [CHIP]) are increased with age and associated with atherosclerosis and inflammation. Age and inflammation are the major risk factors for heart failure, yet the association of CHIP with heart failure in humans is unknown.
To assess the potential prognostic significance of CHIP in patients with chronic heart failure (CHF) owing to ischemic origin.
Design, Setting, and Participants
We analyzed bone marrow–derived mononuclear cells from 200 patients with CHF by deep targeted amplicon sequencing to detect the presence of CHIP and associated such with long-term prognosis in patients with CHF at University Hospital Frankfurt, Frankfurt, Germany. Data were analyzed between October 2017 and April 2018.
Median age of the patients was 65 years. Forty-seven mutations with a variant allele fraction (VAF) of at least 0.02 were found in 38 of 200 patients with CHF (18.5%). The somatic mutations most commonly occurred in the genes DNMT3A (14 patients), TET2 (9 patients), KDM6A (4 patients), and BCOR (3 patients). Patients with CHIP were older and more frequently had a history of hypertension. During a median follow-up of 4.4 years, a total of 53 patients died, and 23 patients required hospitalization for heart failure. There was a significantly worse long-term clinical outcome for patients with either DNMT3A or TET2 mutations compared with non-CHIP carriers. By multivariable Cox proportional regression analysis, the presence of somatic mutations within TET2 or DNMT3A (HR, 2.1; 95% CI, 1.1-4.0; P = .02, for death combined with heart failure hospitalization) and age (HR, 1.04; 95% CI, 1.01-1.07 per year; P = .005) but not a history of hypertension remained independently associated with adverse outcome. Importantly, there was a significant dose-response association between VAF and clinical outcome.
Conclusions and Relevance
Our data suggest that somatic mutations in hematopoietic cells, specifically in the most commonly mutated CHIP driver genes TET2 and DNMT3A, may be significantly associated with the progression and poor prognosis of CHF. Future studies will have to validate our findings in larger cohorts and address whether targeting specific inflammatory pathways may be valuable for precision medicine in patients with CHF carrying specific mutations encoding for CHIP.
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Corresponding Author: Andreas M. Zeiher, MD, Department of Medicine III, Cardiology/Angiology/Nephrology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany (email@example.com).
Accepted for Publication: October 8, 2018.
Published Online: December 19, 2018. doi:10.1001/jamacardio.2018.3965
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Dorsheimer L et al. JAMA Cardiology.
Author Contributions: Drs Zeiher and Rieger had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ms Dorsheimer and Dr Assmus contributed equally as first authors. Drs Dimmeler, Zeiher, and Rieger contributed equally as last authors.
Concept and design: Ortmann, Serve, Dimmeler, Zeiher, Rieger.
Acquisition, analysis, or interpretation of data: Dorsheimer, Assmus, Rasper, Ecke, Abou-El-Ardat, Schmid, Brune, Wagner, Serve, Hoffmann, Seeger, Zeiher, Rieger.
Drafting of the manuscript: Assmus, Zeiher, Rieger.
Critical revision of the manuscript for important intellectual content: Dorsheimer, Rasper, Ortmann, Ecke, Abou-El-Ardat, Schmid, Brune, Wagner, Serve, Hoffmann, Seeger, Dimmeler, Zeiher.
Statistical analysis: Assmus, Ecke, Abou-El-Ardat, Wagner.
Obtained funding: Serve, Dimmeler, Zeiher, Rieger.
Administrative, technical, or material support: Dorsheimer, Rasper, Ortmann, Schmid, Brune, Wagner, Serve, Hoffmann, Seeger.
Supervision: Dorsheimer, Wagner, Serve, Zeiher, Rieger.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Assmus reported personal fees from Novartis, Vifor, Boehringer, and Bayer and grants and personal fees from Abbott outside the submitted work. Dr Serve reported grants from German Cancer Consortium during the conduct of the study. Dr Dimmeler reported grants from BMBF/DZHK during the conduct of the study. Dr. Zeiher reported grants from German Research Foundation and grants from BMBF during the conduct of the study; personal fees from Sanofi, Pfizer, Amgen, and Boehringer Ingelheim; and other fees from T2cure outside the submitted work. Dr Rieger reported grants from Deutsche Forschungsgemeinschaft during the conduct of the study. No other disclosures were reported.
Funding/Support: The study was supported by the German Research Foundation (SFB 834; project B6 to Drs Assmus, Hoffmann, and Zeiher and Z1 to Ms Dorsheimer and Dr Rieger), the Excellence Cluster Cardiopulmonary Systems, project RI2462/1–1 (Dr Rieger), and by the German Center for Cardiovascular Research, Berlin, Germany, partner site Frankfurt Rhine-Main.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Marga Müller-Ardogan, RN, Department of Cardiology, University of Frankfurt, Frankfurt, Germany for excellent technical support and patient care.
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