Medicine in focusIschemic heart disease: Cellular and molecular immune contributions of the pericardium
Introduction
Ischemic heart disease (IHD) is the leading cause of mortality worldwide, accounting for over 7 million deaths annually (World Health Organization, 2014). It is characterized by reduced or complete occlusion of coronary vasculature often due to atherosclerotic plaque development, which can result in myocardial infarction (Lu et al., 2015). The resulting lack of oxygen supply induces tissue injury and necrosis in the infarct zone of the myocardium (Pasotti et al., 2006). Reperfusion of the infarct zone can also induce further tissue damage, which is termed myocardial reperfusion injury (Yellon and Hausenloy, 2007). Due to the limited regenerative capacity of the heart, the loss of heart muscle contributes to loss of function and initiates an ongoing remodeling process. Initially adaptive, this remodeling can contribute to eventual maladaptive changes leading to the development of chronic heart failure (CHF) (Fedak et al., 2005a, Fedak et al., 2005b, Fedak et al., 2005a, Fedak et al., 2005b). The immune response following an MI is a key mediator of this remodeling process (Fig. 1). Both the initial acute infarct and subsequent reperfusion injury are inflammatory events that induce the production of pro-inflammatory markers, such as danger associated molecular patterns (DAMPS) and Reactive Oxygen Species (ROS), and release cytokines and chemokines into the circulation to recruit immune cells into the myocardium and the infarct zone (Nahrendorf et al., 2010, Swirski and Nahrendorf, 2013, Timmers et al., 2012, Yellon and Hausenloy, 2007). In particular, myeloid cells of hematopoietic origin, such as neutrophils and monocytes, have garnered significant attention for their pronounced effect on the duration of the inflammatory response and the post-infarct healing process (Hilgendorf et al., 2014, Nahrendorf et al., 2007, Swirski et al., 2009; Savchenko et al., 2014; Horckmans et al., 2017). Recent studies have shown that tissue resident immune cell populations, namely macrophages, are also determinants of the inflammatory response and the remodeling process (Dick et al., 2019). This highlights the importance of the local environment and homeostatic signals in regulating the health and healing capacity of the heart. The pericardial cavity that surrounds the heart is another homeostatic element important for cardiac performance that has been linked to IHD. This review will provide an update on our understanding of the inflammatory mechanisms of the pericardial space on post-MI remodeling and heart failure
Section snippets
Pericardial cavity composition
It is established that the pericardial cavity is an important determinant of cardiac remodeling, with the mechanical disruption of this compartment contributing to worse cardiac function post-MI (Deniset et al., 2019). This effect is likely multifactorial due to the potential contribution of various elements of this structure. The pericardium is a fibrous sack surrounding the heart and it is filled with fluid. Composed of three layers in humans and two in mice (the serous visceral layer,
Epicardial and pericardial adipose tissue
Beyond the parietal pericardium sits the pericardial adipose tissue (PAT). While often conflated with epicardial adipose tissue (EAT), which resides between the epicardium and the visceral pericardium, PAT is a distinct subset of adipose tissue that differs from EAT. EAT and PAT are derived from different embryological origins (Nagy et al., 2017), and most research on cardiac visceral adipose tissue has focused on EAT. EAT is a metabolically active organ that produces and secretes factors that
Inflammatory profiles in the pericardial fluid: Cardiac biomarkers or local effectors?
Consensus of the origins and composition of pericardial fluid has shifted greatly over time. Originally thought to be just plasma ultrafiltrate (Maurer et al., 1940), the current opinion is that pericardial fluid is a collection of myocardial perfusate, epicardial and pericardial plasma ultrafiltrate, and pericardial secretions from the mesothelium lining the sac (Beltrami et al., 2017, Hoit, 2017, Vogiatzidis et al., 2015). As such, pericardial fluid is often seen as a representative view into
Pericardial-derived immune cells modulate cardiac repair
Our understanding of the cellular contributions of pericardial- and PAT-derived cells in cardiac inflammation and remodeling post-MI has improved in recent years with the use of experimental mouse models (Fig. 2). Similar to the human context, the mouse pericardial compartment contains a broad repertoire of myeloid and lymphoid immune cells (Choi et al., 2020, Deniset et al., 2019, Jackson-Jones et al., 2016). Gata6+ pericardial macrophages (GPCM) make up roughly a third of all immune cells
Modulation of the pericardial space
The pericardium’s accessibility and location relative to the heart, have presented it as a potential vessel for which modulators, such as growth factors and biomaterials, can be inserted into to alter cardiac cellular pathways to improve post infarct healing or attenuate fibrosis. Recent studies have demonstrated the feasibility of using the pericardial space as a delivery vehicle for growth factors, namely fibroblast growth factor (FGF-2), to promote a pro-angiogenic state in the heart after
Conclusions and future directions
It is becoming increasingly apparent that the pericardium is more than a protective sac that provides lubrication and cushion for the heart. The unique homeostatic milieu and immune cell composition of the pericardial fluid and adipose tissue have begun to be shown to have important biological roles in the inflammatory processes of MI.
With current surgical practice involving the disruption of this microenvironment, more study is necessary to understand the role and biological properties of the
Disclosures
The authors have no conflicts to disclose.
Funding
Jameson Dundas holds a Canadian Graduate Scholarship-Master's program from the Canadian Institutes of Health Research (CIHR). Ali Fatehi Hassanabad holds a Vanier Canada Graduate Scholarship from CIHR; a Killam Doctoral Scholarship; and an Alberta Innovates: Health Solutions Doctoral Award.
Acknowledgments
This work was supported by Friederike Schöttler and Vishnu Vasanthan for their assistance with figures.
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