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Ischemic heart disease: Cellular and molecular immune contributions of the pericardium

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Abstract

Ischemic heart disease promotes complex inflammatory and remodeling pathways which contribute to the development of chronic heart failure. Although blood-derived and local cardiac mediators have traditionally been linked with these processes, the pericardial space has more recently been noted as alternative contributor to the injury response in the heart. The pericardial space contains fluid rich in physiologically active mediators, and immunologically active adipose tissue, which are altered during myocardial infarction. Key immune cells in the pericardial fluid and adipose tissue have been identified which act as mediators for cell recruitment and function after myocardial infarction have been identified in experimental models. Here, we provide an overview of the current understanding of the inflammatory mechanisms of the pericardial space and their role in post-myocardial infarction remodeling and the potential for the use of the pericardial space as a delivery vehicle for treatments to modulate heart healing.

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.

References (68)

  • C. Landau et al.

    Intrapericardial basic fibroblast growth factor induces myocardial angiogenesis in a rabbit model of chronic ischemia

    Am. Heart J.

    (1995)
  • Y. Okabe et al.

    Tissue-specific signals control reversible program of localization and functional polarization of macrophages

    Cell

    (2014)
  • A.S. Savchenko et al.

    VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice.

    Blood

    (2014)
  • D.H. Spodick

    Macrophysiology, microphysiology, and anatomy of the pericardium: a synopsis

    Am. Heart J.

    (1992)
  • Y. Uchida et al.

    Angiogenic therapy of acute myocardial infarction by intrapericardial injection of basic fibroblast growth factor and heparin sulfate: an experimental study

    Am. Heart J.

    (1995)
  • X. Yan et al.

    Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction

    J. Mol. Cell. Cardiol.

    (2013)
  • A.S. Antonopoulos et al.

    The role of epicardial adipose tissue in cardiac biology: classic concepts and emerging roles

    J. Physiol.

    (2017)
  • N. Benhaiem-Sigaux et al.

    Characterization of human pericardial macrophages

    J. Leukoc. Biol.

    (1985)
  • M.B. Buechler et al.

    A stromal niche defined by expression of the transcription factor WT1 mediates programming and homeostasis of cavity-resident macrophages

    Immunity

    (2019)
  • H.-X. Chang et al.

    Removal of epicardial adipose tissue after myocardial infarction improves cardiac function

    Herz

    (2018)
  • Y. Chang et al.

    Tissue regeneration observed in a basic fibroblast growth factor-loaded porous acellular bovine pericardium populated with mesenchymal stem cells

    J. Thorac. Cardiovasc. Surg.

    (2007)
  • H.S. Choi et al.

    Innate lymphoid cells play a pathogenic role in pericarditis

    Cell Rep.

    (2020)
  • S. Cruz-Migoni et al.

    Fat-associated lymphoid clusters in inflammation and immunity

    Front. Immunol.

    (2016)
  • J.F. Deniset et al.

    Gata6(+) pericardial cavity macrophages relocate to the injured heart and prevent cardiac fibrosis

    Immunity

    (2019)
  • S.A. Dick et al.

    Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

    Nat. Immunol.

    (2019)
  • A.G.I.M. Elie et al.

    Local enrichment of fatty acid-binding protein 4 in the pericardial cavity of cardiovascular disease patients

    PLoS One

    (2018)
  • A.G.I.M. Elie et al.

    Adipokine imbalance in the pericardial cavity of cardiac and vascular disease patients

    PLoS One

    (2016)
  • A. Fatehi Hassanabad et al.

    Acute Ischemia alters human pericardial-fluid immune cell composition

    J. Am. Coll Cardiol Basic Trans. Sci.

    (2021)
  • M. Fujita et al.

    Elevated basic fibroblast growth factor in pericardial fluid of patients with unstable angina

    Circulation

    (1996)
  • M. Fujita et al.

    Marked elevation of vascular endothelial growth factor and basic fibroblast growth factor in pericardial fluid of patients with angina pectoris

    Angiogenesis

    (1998)
  • S. Greulich et al.

    Secretory products of guinea pig epicardial fat induce insulin resistance and impair primary adult rat cardiomyocyte function

    J. Cell. Mol. Med.

    (2011)
  • D.E. Griffith et al.

    Interleukin-1-mediated release of interleukin-8 by asbestos-stimulated human pleural mesothelial cells

    Am. J. Respir. Cell Mol. Biol.

    (1994)
  • J.J.R. Hermans et al.

    Pharmacokinetic advantage of intrapericardially applied substances in the rat

    J. Pharmacol. Exp. Ther.

    (2002)
  • I. Hilgendorf et al.

    Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium

    Circ. Res.

    (2014)
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