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The Clinical Challenge of Clonal Hematopoiesis, a Newly Recognized Cardiovascular Risk Factor

Educational Objective
To review the pathogenesis and cardiovascular risk profile of clonal hematopoiesis.
1 Credit CME
Abstract

Importance  Despite current standards of cardiovascular care, a considerable residual burden of risk remains in both primary and secondary prevention. Clonal hematopoiesis of indeterminate potential (CHIP) has recently emerged as a common, potent, age-associated, independent risk factor for myocardial infarction, stroke, heart failure events, and survival following percutaneous aortic valve intervention. The presence of CHIP results from the acquisition of somatic mutations in a small number of leukemia driver genes found in bone marrow stem cells, leading to the expansion of leukocytes clones in peripheral blood. The association between CHIP and cardiovascular disease likely involves activation of the inflammasome pathway. More common DNA sequencing identifies individuals with CHIP who then seek advice regarding management of their cardiovascular risk.

Observations  Using clinical vignettes based on real encounters, we highlight some of the diverse presentations of CHIP, ranging from incidental identification to that detected during cancer care, that have brought patients to the attention of cardiovascular practitioners. We illustrate how we have applied a consensus-based approach to the evaluation and management of cardiovascular risk in specific patients with CHIP. Since we currently lack evidence to guide the management of these individuals, we must rely on expert opinion while awaiting data to furnish a firmer foundation for our recommendations.

Conclusions and Relevance  These vignettes illustrate that the management of CHIP should involve an individualized plan based on features such as comorbidities, life expectancy, and other traditional cardiovascular risk factors. Because individuals with CHIP will increasingly seek advice from cardiovascular specialists regarding management, these examples provide a template for approaches based on a multidisciplinary perspective. The current need for reliance on expert opinion illustrates a great need for further investigation into the management of this newly recognized contributor to residual cardiovascular risk, both in patients who are apparently well and those with established cardiovascular or malignant disease.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: March 18, 2020.

Corresponding Author: Peter Libby, MD, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA 02115 (plibby@bwh.harvard.edu).

Published Online: May 27, 2020. doi:10.1001/jamacardio.2020.1271

Author Contributions: Dr Libby had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Lin, Steensma, Libby.

Drafting of the manuscript: Sidlow, Lin, Gupta, Bolton, Libby.

Critical revision of the manuscript for important intellectual content: Lin, Bolton, Steensma, Levine, Ebert, Libby.

Statistical analysis: Libby.

Obtained funding: Libby.

Administrative, technical, or material support: Libby.

Supervision: Gupta, Libby.

Other: Bolton.

Conflict of Interest Disclosures: Dr Libby is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Pfizer, Sanofi-Regeneron, and XBiotech Inc; is a member of scientific advisory boards for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, IFM Therapeutics, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, and XBiotech Inc; serves on the board of Xbiotech Inc; and has received laboratory has research funding in the last 2 years from Novartis. Dr Ebert has received consulting fees from GRAIL and research funding from Celgene and Deerfield. Dr Steensma reports independent data safety monitoring committee service for Onconova, Janssen, Takeda, and Pharmessentia; institutional research funding for trials on which he is local or overall principal investigator from H3 Biosciences, Aprea, Celgene Consulting: Sensei, Otsuka, and Stemline. Dr Levine is on the supervisory board of Qiagen and a scientific advisor to Loxo, Imago, C4 Therapeutics, and Isoplexis, which each include an equity interest; receives research support from and has consulted for Celgene and Roche; has received research support from Prelude Therapeutics; has consulted for Incyte, Novartis, Astellas, Morphosys, and Janssen; and has received honoraria from Lilly and Amgen for invited lectures and Gilead for grant reviews. No other disclosures were reported.

Funding/Support: Dr Libby is funded by the National Heart, Lung, and Blood Institute (grant R01HL080472); the American Heart Association (grant 18CSA34080399); and the RRM Charitable Fund. Dr Sidlow is supported by the National Cancer Institute Cancer Center Support Grant (grant P30 CA008748). Dr Lin is supported by the John S. LaDue Memorial Fellowship in Cardiology. Dr Bolton received funding from GRAIL. Dr Steensma reports funding from the Edward P Evans Foundation and the James and Lois Champy Fund. Dr Levine was supported in part by a Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). Dr Ebert reports funding from the Leducq Foundation and the Howard Hughes Medical Institute. Dr Gupta is supported by a National Cancer Institute Cancer Center Support Grant (P30 CA008748).

Role of the Funder/Sponsor: The funders 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 Information: Drs Lin, Ebert, and Libby are members of the Leducq Transatlantic Network on Clonal Hematopoiesis.

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