Increased mast cell density is associated with decreased fibrosis in human atrial tissue
Graphical abstract
Introduction
Myocardial fibrosis is the accumulation of extracellular matrix components, such as collagen, within the myocardium. This process accompanies many forms of heart disease and is associated with poor patient outcomes [1]. However, some fibrosis is necessary for proper wound healing after myocardial injury, such as myocardial infarction or hypertension-induced stretch injury. Fibrosis can occur in all chambers of the heart and is often associated with myocardial stiffening and reduced signal transduction that ultimately leads to heart failure [2]. Understanding myocardial fibrosis requires better characterization of the fibrotic microenvironment for the development of future therapeutic strategies.
Evidence suggests that myocardial fibrosis is driven by dysregulated inflammation [1], implicating the immune system is a contributor to its pathogenesis. Resident immune cells, such as mast cells and macrophages, are thought to contribute to fibrotic remodelling in response to damage to the myocardium indirectly [3] or directly [4,5]. Mast cells are innate immune sentinel cells that respond to a variety of stimuli, including damage-associated alarmins [6], through a wide array of pattern recognition and mediator receptors. Upon activation, mast cells can degranulate to release stores of preformed mediators, or secrete a variety of compounds de novo with or without degranulation [7]. After myocardial injury, mast cell density is increased in animal models [8,9]. However, the exact role of mast cells in the pathogenesis of myocardial fibrosis is not well understood. Both beneficial and detrimental roles have been suggested [10,11], as various mast cell mediators have been shown to have pro- and anti-fibrotic effects [10]. Previous studies have often only considered mast cell degranulation as evidence of activity. Mast cell granule contents are known to contain pro-fibrotic compounds such as chymase, tryptase, and TGF-β. However, as previously mentioned, mast cells can respond to stimuli released in the heart after damage without degranulation. Mast cells have been shown to produce anti-fibrotic compounds, such as CXCL10 [12,13], VEGF-A [14], and IL-33 [7,15], in other disease settings, yet it is unknown if these mediators are up-regulated by mast cells after myocardial damage. Studies in mice have been controversial, partly due to fundamental differences in the distribution and phenotype of myocardial mast cell populations between mice and humans, and their ontogeny as resident or itinerant populations [16]. To date, few studies have examined mast cells in human chronic cardiovascular disease [[17], [18], [19], [20], [21]].
Therapeutic approaches to limiting myocardial fibrosis have largely focused on blocking canonical pro-fibrotic pathways, such as the Renin-Angiotensin-Aldosterone System (RAAS) [22], rather than inducing anti-fibrotic mediators. There is increased recognition of the importance of inflammation in the pathogenesis of cardiovascular disease as a whole [13] including myocardial fibrosis [1]. Mast cells can respond to a wealth of stimuli [7,23,24] to maintain homeostasis, and quickly respond to infection or damage, shaping the inflammatory response that follows. Therefore, we hypothesize that mast cells could play a critical role in regulating cardiac remodelling and as such, they could provide an important cellular mechanism determining the nature of fibrosis and tissue restitution following cardiac damage [7,10].
The current study examined the relationship between mast cells and myocardial fibrosis using tissues from cardiac surgery patients with established cardiovascular disease. Human right atrial appendage tissue was excised during cardiac surgical procedures and used to provide insight into fibrotic remodelling and resident mast cells. Detailed preoperative and postoperative variables were collected in all patients to determine how mast cell density from tissue samples could relate to patient outcomes. This study demonstrates an association between high levels of atrial tissue mast cells, reduced fibrosis, and improved functional outcomes. These data indicate that increased mast cell density provides a cellular mechanism for reducing myocardial fibrosis in human patient samples.
Section snippets
Study procedures and human atrial tissue samples acquisition
Blood samples were collected from all patients prior to skin incision and atrial tissue samples were taken at the time of cannulation. A portion of right atrial appendage was excised during surgery and processed for RNA, protein, and histological analyses. Cardiac surgery was performed with cardiopulmonary bypass and anticoagulation was achieved using intravenous heparin (400 IU/kg) with a target activated clotting time (ACT) greater than 450 s. Antifibrinolytic agents were given to all
Mast cells are present in varying numbers in human atria
Human atrial tissue samples were obtained while patients (n = 112) underwent cardiac surgery at two centres in Atlantic Canada (Halifax, NS, and Saint John, NB). The procedures performed included: isolated CABG (54%), isolated valve (21%), and combined CABG/valve (25%). The average heart function (defined by ejection fraction, EF) for the entire cohort of patients was 58% ± 13%, with the majority (94%) having a normal EF (defined as ≥50%). A significant proportion of patients (40.2%) were
Discussion
This study identifies an association between increased mast cell numbers and reduced cardiac fibrosis. This could indicate a potential role for mast cells as negative regulators of myocardial fibrosis or suggest that increased mast cells are functionally hallmarks of an anti-fibrotic process in which they do not directly participate. Patients identified to be within the upper quartile for atrial mast cell density at the time of cardiac surgery, had significantly less collagen in their atrial
Author contributions
SAL - Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Validation; Visualization; Writing - original draft; Writing - review & editing
IDH - Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Supervision; Writing - review & editing
MCC - Formal analysis; Methodology; Resources; Writing - review & editing
KB - Formal analysis; Funding acquisition; Investigation; Methodology; Project
Acknowledgements and funding sources
We would like to acknowledge Alexander Edgar, Nong Xu, Alec Falkenham, Tanya Myers, Chloe Wong, Kareem Gawdat, Lester Perez-Rodriguez, Christie Aguiar, Ansar Hassan, Thomas Pulinilkunnil, Petra Kienesberger, Jeffrey MacLeod, and Hany Motawea for their contributions to this manuscript as well as all nurses and nurse associates that enabled patient recruitment and clinical sampling/tissues collections obtained from the IMPART investigator team Canada BioBank (https://impart.team/) for their
Declaration of Competing Interest
The authors declare that they do not have any competing interests pertaining to the work detailed in this manuscript.
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