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J Am Coll Cardiol. 2019 Jul 30;74(4):578-586. doi: 10.1016/j.jacc.2019.05.045.

Clonal Hematopoiesis of Indeterminate Potential Reshapes Age-Related CVD: JACC Review Topic of the Week.

Author information

1
Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts.
2
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
3
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
4
Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Verve Therapeutics, Cambridge, Massachusetts.
5
Department of Pathology, Stanford University School of Medicine, Palo Alto, California.
6
Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. Electronic address: pnatarajan@mgh.harvard.edu.

Abstract

The incidence of cardiovascular diseases increases with age and is also correlated with increased inflammatory burden. Recently, human genetics provided a new paradigm linking aging, inflammation, and atherosclerotic cardiovascular disease (ASCVD). Next-generation genetic sequencing of whole blood-derived DNA in humans showed that clonal expansion of hematopoietic cells with somatic mutations in leukemogenic genes was associated with age and correlated with increased mortality. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), was associated with hematologic malignancy as well as ASCVD independently of age and other traditional risk factors. Because the implication of CHIP with ASCVD, genetic loss-of-function studies of Tet2 and Dnmt3a in murine models have supported a mechanistic role for CHIP in promoting vascular disease. Despite the potential contribution of CHIP to myriad cardiovascular and aging-related diseases, the epidemiology and biology surrounding this phenomenon remains incompletely appreciated and understood, especially as applied to clinical practice and prognostication. Here, the authors review this emerging key risk factor, defining its discovery, relationship to cardiovascular diseases, preclinical evidence for causality, and implications for risk prediction and mitigation.

KEYWORDS:

aging; atherosclerotic cardiovascular disease; clonal hematopoiesis of indeterminate potential; coronary heart disease; diabetes mellitus; heart failure; hematopoietic stem cell; inflammation; myelopoiesis; somatic mutations; venous thromboembolism

PMID:
31345433
PMCID:
PMC6662618
[Available on 2020-07-30]
DOI:
10.1016/j.jacc.2019.05.045

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