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  • Hematopoietic Somatic Mosaicism Associated with Increased AF Risk

    Assessment of patients for hematopoietic somatic mosaicism (HSM) genes may be useful in the personalized management of aortic valve replacement (AVR) patients, according to new research that identifies a high prevalence of HSM in surgical candidates.

    The study, published online Monday and in the April 4 issue of the Journal of the American College of Cardiology, notes that HSM is a recently identified risk factor for cardiovascular diseases – adding that low-frequency mutations in a selection of HSM genes, termed “clonal hematopoiesis of indeterminate potential” (CHIP) genes, have been associated with adverse clinical outcomes such as coronary artery disease, chronic heart failure, incident atrial fibrillation (AF), and mortality following percutaneous AVR.

    Led by Sandro Ninni, MD, PhD, from the Institut Pasteur de Lille at the Université de Lille, France, the new data reveal that HSM is frequent in patients undergoing cardiac surgery – showing that its prevalence critically depends on the gene number included in the definition, with the broadest definition identifying patients at very high risk for postoperative atrial fibrillation (POAF) following surgery.

    “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,” they said, noting that HSM most frequently occurs in two genes (DNMT3A and TET2) encoding epigenetic regulators.

    “Assessment of HSM and/or its related alterations in monocytes might thus be valuable indicators to personalize management in the context of cardiac surgery,” they said.

    Study setup

    Ninni and colleagues noted that 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.

    The team performed blood DNA genotyping using the HemePACT panel (576 genes) in 104 patients referred for surgical AVR. Within the analysis, four screening methods were applied to assess HSM, and postoperative outcomes were explored.

    “To assess the correlation of HSM with age and clinical outcomes, 4 different definitions were adopted. These definitions are based upon different gene sets reported in previous studies,” the team noted.

    “For each gene set, according to previous studies, 2 VAF [variant allelic frequency] thresholds were assessed (2% and 1%) to evaluate the relevance of low VAF and its correlations with age and POAF. Thus, 4 definitions for HSM were determined on the basis of these 2 combined criteria: 1) conventional CHIP panel, VAF ≤2%; 2) conventional CHIP panel, VAF ≤1%; 3) HemePACT panel, VAF ≤2%; and 4) HemePACT panel, VAF ≤1%.”

    The team also performed in-depth blood and myocardial leukocyte phenotyping in selected patients using mass cytometry and preoperative and postoperative RNA sequencing analysis of classical monocytes.

    Key findings

    Analysis based on the above four HSM definitions resulted in an overall high prevalence of HSM, ranging from 29% to 60% of patients (29% for the conventional CHIP panel with VAF ≤2%, 45% for the conventional CHIP panel with VAF ≤1%, 44% for the HemePACT panel with VAF ≤2%, and 60% for the HemePACT panel with VAF ≤1%)

    “Importantly, these HSM carriers had a 3.5-fold higher risk for POAF even after adjustment for age (age-adjusted OR [odds ratio]: 3.5; 95% CI [confidence interval]: 1.52-8.03; P = 0.003). This association between HSM and POAF was found for all 4 HSM definitions, although it was only borderline significant with the conventional CHIP panel with VAF ≤2,” the team said.

    Moreover, Ninni and colleagues found that the presence of HSM was associated with an increased count of circulating monocytes – specifically inflammatory CD64+ monocytes – circulating classical inflammatory monocyte gene profiles indicative of activation and chemotaxis, and an increase in monocyte-derived CD64+ inflammatory macrophages in the myocardium.

    “In line, HSM carriers display a more pronounced perioperative inflammatory response with a higher incidence of POAF independently of age and other confounders,” they noted, adding that the study “highlights critical variations in HSM prevalence depending on the screening methods used.”

    Macrophage mechanism?

    Writing in an accompanying editorial, Ziad Mallat, MD, PhD, from the University of Cambridge, noted that POAF is a frequent complication of thoracic surgery and is associated with immediate adverse outcomes, including increased risk for stroke and hemodynamic instability, prolonged hospital stay, and increased hospital costs.

    He noted that CHIP recently sparked interest in the cardiovascular community after it was found to be associated with an increased risk for atherosclerotic cardiovascular disease – adding that further studies have now reported significant associations between CHIP and a number of additional cardiovascular conditions, including heart failure and increased mortality after transcatheter AVR.

    “The results of Ninni et al support the hypothesis that monocytes and macrophages are involved in POAF, and potentially AF in general, and that these immune cells may constitute a causal link between CHIP and (PO)AF,” he said, noting that the team “should be congratulated on an interesting and thought-provoking work.”

    “The role of CHIP in driving the pathogenesis of (PO)AF certainly merits further attention,” he added.

    Sources:

    Ninni S, Dombrowicz D, Kuznetsova T, et al. Hematopoietic Somatic Mosaicism Is Associated With an Increased Risk of Postoperative Atrial Fibrillation. J Am Coll Cardiol 2023;81:1263-1278.

    Mallat Z. Fishing CHIPs to Predict Postoperative Atrial Fibrillation. J Am Coll Cardiol 2023;81:1279-1282.

    Image Credit: freshidea – stock.adobe.com

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