Original Investigation
Hematopoietic Somatic Mosaicism Is Associated With an Increased Risk of Postoperative Atrial Fibrillation

https://doi.org/10.1016/j.jacc.2023.01.036Get rights and content

Abstract

Background

On-pump cardiac surgery triggers sterile inflammation and postoperative complications such as postoperative atrial fibrillation (POAF). Hematopoietic somatic mosaicism (HSM) is a recently identified risk factor for cardiovascular diseases and results in a shift toward a chronic proinflammatory monocyte transcriptome and phenotype.

Objectives

The aim of this study was to assess the prevalence, characteristics, and impact of HSM on preoperative blood and myocardial myeloid cells as well as on outcomes after cardiac surgery.

Methods

Blood DNA from 104 patients referred for surgical aortic valve replacement (AVR) was genotyped using the HemePACT panel (576 genes). Four screening methods were applied to assess HSM, and postoperative outcomes were explored. In-depth blood and myocardial leukocyte phenotyping was performed in selected patients using mass cytometry and preoperative and postoperative RNA sequencing analysis of classical monocytes.

Results

The prevalence of HSM in the patient cohort ranged from 29%, when considering the conventional HSM panel (97 genes) with variant allelic frequencies ≥2%, to 60% when considering the full HemePACT panel and variant allelic frequencies ≥1%. Three of 4 explored HSM definitions were significantly associated with higher risk for POAF. On the basis of the most inclusive definition, HSM carriers exhibited a 3.5-fold higher risk for POAF (age-adjusted OR: 3.5; 95% CI: 1.52-8.03; P = 0.003) and an exaggerated inflammatory response following AVR. HSM carriers presented higher levels of activated CD64+CD14+CD16 circulating monocytes and inflammatory monocyte-derived macrophages in presurgery myocardium.

Conclusions

HSM is frequent in candidates for AVR, is associated with an enrichment of proinflammatory cardiac monocyte–derived macrophages, and predisposes to a higher incidence of POAF. HSM assessment may be useful in the personalized management of patients in the perioperative period. (Post-Operative Myocardial Incident & Atrial Fibrillation [POMI-AF]; NCT03376165)

Section snippets

Cohort and preoperative clinical assessment

The clinical cohort is part of the POMI-AF (Post-Operative Myocardial Incident & Atrial Fibrillation; NCT03376165) study, approved by the institutional ethics committee (Comité de Protection des Personnes Ile de France V). Written informed consent was obtained from all patients before inclusion.

Patients (≥18 years of age) were referred to the cardiovascular surgery department at Lille University Hospital for AVR (with or without coronary artery bypass grafting) because of severe aortic valve

HSM is highly prevalent in patients undergoing cardiac surgery

HSM was assessed using deep targeted DNA sequencing of leukocytes from 104 patients (52 with POAF and 52 in sinus rhythm) elected for AVR using a large panel of 576 genes (HemePACT panel) (Supplemental Table 2). The median age of the 104 patients was 70 years (IQR: 66-75 years), 36% were women, and 29% had type 2 diabetes mellitus. As a result of the patient selection process, patients with POAF and those in sinus rhythm had comparable distributions regarding age, BMI, diabetic status, and sex (

Discussion

Our results show that patients undergoing cardiac surgery display a high prevalence of HSM (as high as 60% with the most inclusive definition), which increases with age. HSM most frequently occurs in 2 genes (DNMT3A and TET2) encoding epigenetic regulators. Moreover, we found that the presence of HSM is associated with: 1) increased circulating monocyte counts, specifically inflammatory CD64+ monocytes; 2) circulating classical inflammatory monocyte gene profiles indicative of activation and

Conclusions

HSM is frequent in patients undergoing cardiac surgery. Its prevalence critically depends on the gene number included in the definition, with the broadest definition identifying patients at very high risk for POAF following surgery. This increased risk for POAF could be related to an increased postoperative inflammatory response driven by primed monocytes and increased atrial vulnerability driven by an immune shift in the atrial myocardium (Central Illustration). Assessment of HSM and/or its

Funding Support and Author Disclosures

This study was supported by grants from Fédération Française de Cardiologie, Fondation Leducq convention 16CVD01 (“Defining and Targeting Epigenetic Pathways in Monocytes and Macrophages That Contribute to Cardiovascular Disease”), the European Genomic Institute for Diabetes (ANR-10-LABX-0046), Fondation Pour la Recherche Médicale (REFERENCE PROJET EQU202203014650), and Agence Nationale de la Recherche (TOMIS leukocytes: ANR-CE14-0003-01). Dr Staels is a recipient of an Advanced European

Acknowledgments

The authors thank Bertrand Accart and the Biological Resources Center of Centre Hospitalier de Lille (BB 0033-00030) for handling and providing biological samples from the POMI-AF study.

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    The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

    Drs Ninni, and Dombrowicz are co-first authors.

    Drs Kuznetsova and Vicario are co-second authors.

    Drs Staels and Montaigne are co–senior authors.

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