Clonal hematopoiesis is associated with cardiovascular events in patients with stable coronary artery disease
Mihaela I. Dregoesc,
Helin Tercan,
Adrian B. Țigu,
Siroon Bekkering,
Leo AB. Joosten,
Mihai G. Netea,
Rosanne C. van Deuren,
Alexander Hoischen,
Niels P. Riksen,
Adrian C. Iancu
Affiliations
Mihaela I. Dregoesc
“Iuliu Hatieganu” University of Medicine and Pharmacy, Department of Cardiology –“Niculae Stăncioiu” Heart Institute, 19-21 Calea Moților, 400001 Cluj-Napoca, Romania
Helin Tercan
Radboud University Medical Center, Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, the Netherlands
Adrian B. Țigu
MEDFUTURE Research Center for Advanced Medicine, Department of Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 4-6 Louis Pasteur, 400349 Cluj-Napoca, Romania
Siroon Bekkering
Radboud University Medical Center, Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, the Netherlands
Leo AB. Joosten
Radboud University Medical Center, Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, 4-6 Louis Pasteur, 400349 Cluj-Napoca, Romania
Mihai G. Netea
Radboud University Medical Center, Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
Rosanne C. van Deuren
Radboud University Medical Center, Department of Human Genetics, Geert Grooteplein Zuid 855, 6525 GA Nijmegen, the Netherlands
Alexander Hoischen
Radboud University Medical Center, Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, the Netherlands; Radboud University Medical Center, Department of Human Genetics, Geert Grooteplein Zuid 855, 6525 GA Nijmegen, the Netherlands; Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, the Netherlands
Niels P. Riksen
Radboud University Medical Center, Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, the Netherlands; Corresponding author
Adrian C. Iancu
“Iuliu Hatieganu” University of Medicine and Pharmacy, Department of Cardiology –“Niculae Stăncioiu” Heart Institute, 19-21 Calea Moților, 400001 Cluj-Napoca, Romania; Corresponding author
Summary: Clonal hematopoiesis (CH) is a risk factor for atherosclerotic cardiovascular disease, but the impact of smaller clones and the effect on inflammatory parameters is largely unknown. Using ultrasensitive single-molecule molecular inversion probe sequencing, we evaluated the association between CH and a first major adverse cardiovascular event (MACE) in patients with angiographically documented stable coronary artery disease (CAD) and no history of acute ischemic events. CH was associated with an increased rate of MACE at four years follow-up. The size of the clone predicted MACE at an optimal cut-off value of 1.07% variant allele frequency (VAF). Mutation carriers had no change in monocytes subsets or cytokine production capacity but had higher levels of circulating tissue factor, matrilysin, and proteinase-activated receptor-1. Our study identified CH driver mutations with a VAF as small as 1.07% as a residual cardiovascular risk factor and identified potential biomarkers and therapeutic targets for patients with stable CAD.
