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<journal-id journal-id-type="publisher-id">Front. Cardiovasc. Med.</journal-id>
<journal-title>Frontiers in Cardiovascular Medicine</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cardiovasc. Med.</abbrev-journal-title>
<issn pub-type="epub">2297-055X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcvm.2024.1329767</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cardiovascular Medicine</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Novel role of cardiovascular MRI to contextualise tuberculous pericardial inflammation and oedema as predictors of constrictive pericarditis</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes"><name><surname>Giliomee</surname><given-names>L. J.</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="corresp" rid="cor1">&#x002A;</xref><uri xlink:href="https://loop.frontiersin.org/people/2558256/overview"/>
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<contrib contrib-type="author"><name><surname>Doubell</surname><given-names>A. F.</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:href="https://loop.frontiersin.org/people/2133746/overview" />
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<contrib contrib-type="author"><name><surname>Robbertse</surname><given-names>P. S.</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:href="https://loop.frontiersin.org/people/2664754/overview" />
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<contrib contrib-type="author"><name><surname>John</surname><given-names>T. J.</given-names></name>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
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<contrib contrib-type="author"><name><surname>Herbst</surname><given-names>P. G.</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:href="https://loop.frontiersin.org/people/2390866/overview" />
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<aff id="aff1"><label><sup>1</sup></label><institution>Division of Cardiology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital</institution>, <addr-line>Bellville</addr-line>, <country>South Africa</country></aff>
<aff id="aff2"><label><sup>2</sup></label><institution>Heart Unit, Mediclinic Panorama, Cape Town</institution>, <country>South Africa</country></aff>
<author-notes>
<fn fn-type="edited-by"><p><bold>Edited by:</bold> Nazario Carrabba, Careggi Hospital, Italy</p></fn>
<fn fn-type="edited-by"><p><bold>Reviewed by:</bold> Nikhil Agrawal, University of Texas Health Science Center at Houston, United States</p>
<p>Stefano Figliozzi, St Thomas&#x2019; Hospital, United Kingdom</p></fn>
<corresp id="cor1"><label>&#x002A;</label><bold>Correspondence:</bold> L. J. Giliomee <email>giliomeelj13@gmail.com</email></corresp>
</author-notes>
<pub-date pub-type="epub"><day>18</day><month>03</month><year>2024</year></pub-date>
<pub-date pub-type="collection"><year>2024</year></pub-date>
<volume>11</volume><elocation-id>1329767</elocation-id>
<history>
<date date-type="received"><day>29</day><month>10</month><year>2023</year></date>
<date date-type="accepted"><day>23</day><month>02</month><year>2024</year></date>
</history>
<permissions>
<copyright-statement>&#x00A9; 2024 Giliomee, Doubell, Robbertse, John and Herbst.</copyright-statement>
<copyright-year>2024</copyright-year><copyright-holder>Giliomee, Doubell, Robbertse, John and Herbst</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License (CC BY)</ext-link>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license>
</permissions>
<abstract>
<p>Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syndrome have reached epidemic proportions, particularly affecting vulnerable populations in low- and middle-income countries of sub-Saharan Africa. TB pericarditis is the commonest cardiac manifestation of TB and is the leading cause of constrictive pericarditis, a reversible (by surgical pericardiectomy) cause of diastolic heart failure in endemic areas. Unpacking the complex mechanisms underpinning constrictive haemodynamics in TB pericarditis has proven challenging, leaving various basic and clinical research questions unanswered. Subsequently, risk stratification strategies for constrictive outcomes have remained unsatisfactory. Unique pericardial tissue characteristics, as identified on cardiovascular magnetic resonance imaging, enable us to stage and quantify pericardial inflammation and may assist in identifying patients at higher risk of tissue remodelling and pericardial constriction, as well as predict the degree of disease reversibility, tailor medical therapy, and determine the ideal timing for surgical pericardiectomy.</p>
</abstract>
<kwd-group>
<kwd>TB pericarditis</kwd>
<kwd>constrictive pericarditis</kwd>
<kwd>pericardial inflammation</kwd>
<kwd>pericardial oedema</kwd>
<kwd>CMR</kwd>
<kwd>pericardial effusion</kwd>
<kwd>risk stratification</kwd>
<kwd>diastolic cardiac dysfunction</kwd>
</kwd-group><counts>
<fig-count count="6"/>
<table-count count="0"/><equation-count count="0"/><ref-count count="42"/><page-count count="0"/><word-count count="0"/></counts><custom-meta-wrap><custom-meta><meta-name>section-at-acceptance</meta-name><meta-value>Cardiovascular Imaging</meta-value></custom-meta></custom-meta-wrap>
</article-meta>
</front>
<body><sec id="s1" sec-type="intro"><title>Introduction</title>
<p>The pericardial sac surrounds the heart in a unique double-layered manner, containing a small amount of fluid between these layers, and it serves to both stabilise the heart and provide a favourable environment to ensure minimal friction during each cardiac cycle (<xref ref-type="bibr" rid="B1">1</xref>). Tuberculosis (TB), the most common cause of pericardial constriction in endemic areas (<xref ref-type="bibr" rid="B2">2</xref>&#x2013;<xref ref-type="bibr" rid="B5">5</xref>), can however disrupt this favourable environment, leading to a state of severe inflammation dominated by maladaptive tissue remodelling, fibrosis, and calcification (<xref ref-type="bibr" rid="B6">6</xref>&#x2013;<xref ref-type="bibr" rid="B8">8</xref>). As a result, the heart becomes encased with impaired diastolic cardiac filling, characterising constrictive pericarditis (CP) (<xref ref-type="bibr" rid="B9">9</xref>, <xref ref-type="bibr" rid="B10">10</xref>).</p>
<p>Chronic CP represents an irreversible state of haemodynamic compromise and is an indication for pericardiectomy, as untreated cases exhibit poor outcomes (<xref ref-type="bibr" rid="B9">9</xref>). While potentially curative, pericardiectomy carries high surgical risk, with significant peri- and post-operative morbidity and mortality (<xref ref-type="bibr" rid="B9">9</xref>&#x2013;<xref ref-type="bibr" rid="B12">12</xref>). Early diagnosis and treatment, particularly when pericardial constriction is less advanced and associated with less fibro-calcification, lead to better surgical outcomes (<xref ref-type="bibr" rid="B13">13</xref>). On the other hand, premature intervention carries the risk of exposure to unnecessary surgery, as the dynamic inflammatory component seen in effusive-constrictive pericarditis (ECP) is typically reversible (<xref ref-type="bibr" rid="B14">14</xref>, <xref ref-type="bibr" rid="B15">15</xref>). Therefore, optimal surgical timing is crucial to ensure favourable patient outcomes, but it remains challenging and often elusive in clinical practice.</p>
<p>This case-based review aims to illustrate the potential of new cardiovascular magnetic resonance (CMR) imaging data, which enables the staging and quantification of pericardial inflammation (<xref ref-type="bibr" rid="B16">16</xref>), in offering significant improvements in prognostication by identifying patients at higher risk for developing pericardial constriction. It may also guide clinical decision-making to optimise medical and surgical interventions and assist in determining the optimal timing for pericardiectomy.</p>
</sec>
<sec id="s2"><title>Case 1</title>
<p>A 36-year-old human immunodeficiency virus (HIV)-uninfected man presented with a 2-week history of dyspnoea, constitutional symptoms, and clinical findings suggestive of a pericardial effusion.</p>
<p>The diagnosis of a large circumferential pericardial effusion was confirmed via transthoracic echocardiogram (TTE), and a pericardiocentesis was performed, which confirmed a definitive diagnosis of rifampicin-sensitive TB pericarditis (<xref ref-type="bibr" rid="B17">17</xref>). Despite maximal drainage of the pericardial effusion (&#x003E;1,000&#x2005;ml), constrictive physiology (<xref ref-type="bibr" rid="B18">18</xref>) persisted, further classifying this case as ECP (<xref ref-type="bibr" rid="B19">19</xref>).</p>
<p>He was subsequently initiated on the local first-line anti-tuberculous chemotherapy regimen (<xref ref-type="bibr" rid="B20">20</xref>) without adjunctive anti-inflammatory therapy and was scheduled for review at 3-month intervals.</p>
<p>At the 3-month follow-up, he exhibited clinical features of predominantly right heart failure despite being compliant with his anti-tuberculous chemotherapy, and a diagnosis of constrictive pericarditis was confirmed via TTE (<xref ref-type="bibr" rid="B18">18</xref>, <xref ref-type="bibr" rid="B19">19</xref>, <xref ref-type="bibr" rid="B21">21</xref>).</p>
<p>A CMR study was performed, which demonstrated severe residual pericardial inflammation, as evidenced by diffuse, circumferential hyperenhancement of the thickened pericardium observed on late gadolinium enhancement (LGE) imaging (see <xref ref-type="fig" rid="F1">Figure&#x00A0;1A</xref>). Areas of residual pericardial oedema were also identified, as demonstrated by the focal areas of increased T2 short tau inversion recovery (STIR) and T2 mapping signal (see arrows in <xref ref-type="fig" rid="F1">Figures&#x00A0;1B,C</xref>), without any re-accumulation of the pericardial effusion. In addition, CMR confirmed constrictive physiology on free-breathing real-time cine sequences (<xref ref-type="bibr" rid="B22">22</xref>&#x2013;<xref ref-type="bibr" rid="B24">24</xref>).</p>
<fig id="F1" position="float"><label>Figure 1</label>
<caption><p>Case 1: 3-month CMR findings&#x2014;sub-acute TB pericarditis with marked residual pericardial inflammation. (<bold>A</bold>) LGE image showing an intense circumferential pericardial signal indicative of marked circumferential pericardial inflammation. (<bold>B</bold>) T2-STIR and (<bold>C</bold>) T2 mapping images showing a high pericardial signal of segments overlying the LV lateral and anterior walls and anterior to the right ventricular (RV) free wall (indicated by arrows), with normal pericardial signal intensity of the other pericardial segments. Marked pericardial inflammation (<bold>A</bold>) demonstrates a risk of continued tissue remodelling and pericardial fibrosis; however, oedematous segments with acute pericarditis (arrows in <bold>B</bold>,<bold>C</bold>) represent reversible constrictive haemodynamics.</p></caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="fcvm-11-1329767-g001.tif"/>
</fig>
<p>Based on the presence of constrictive physiology 3 months after the initiation of anti-tuberculous chemotherapy and in accordance with expert consensus recommending optimal surgical timing to be 6&#x2013;8 weeks after the initiation of anti-tuberculous chemotherapy, the patient was referred for surgical pericardiectomy (<xref ref-type="bibr" rid="B25">25</xref>).</p>
<p>However, the patient declined surgical intervention at this time, and the best medical therapy was continued (anti-tuberculous chemotherapy and diuretics) in addition to planning further clinical follow-up.</p>
<p>After 4 months of anti-tuberculous chemotherapy, the patient was found to be asymptomatic with complete resolution of symptoms and free from all signs of constrictive physiology on repeat TTE, despite the patient having stopped his diuretic therapy in the weeks preceding this follow-up.</p>
<p>Repeat CMR confirmed the complete resolution of pericardial oedema on T2-STIR imaging and T2 mapping (see <xref ref-type="fig" rid="F2">Figures&#x00A0;2B,C</xref>), with minimal residual pericardial inflammatory signal seen on LGE sequences (see <xref ref-type="fig" rid="F2">Figure&#x00A0;2A</xref>).</p>
<fig id="F2" position="float"><label>Figure 2</label>
<caption><p>Case 1: 4-month CMR findings&#x2014;burnt-out TB pericarditis. (<bold>A</bold>) LGE image showing normal pericardial signal intensity indicative of complete resolution of pericardial inflammation. (<bold>B</bold>) T2-STIR and (<bold>C</bold>) T2 mapping images showing normal pericardial signal intensities indicative of absent pericardial oedema. A burnt-out (resolved pericardial inflammation and oedema) CMR picture of TB pericarditis in the setting of non-constrictive haemodynamics is an indication that medical therapy can be stopped (or can be stopped as soon as the patient has completed the standard 6-month anti-tuberculous chemotherapy course) and that a pericardiectomy is not indicated.</p></caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="fcvm-11-1329767-g002.tif"/>
</fig>
<sec id="s2a"><title>Case 1: discussion</title>
<p>ECP is an umbrella term used to describe the presence of constrictive physiology after drainage of a large pericardial effusion (<xref ref-type="bibr" rid="B19">19</xref>). Increased pericardial stiffness in this setting results from a variable contribution of (1) acute pericardial inflammation and oedema and (2) established pericardial scarring, which cumulatively result in physiologically significant constrictive haemodynamics, persisting despite the drainage of pericardial fluid (<xref ref-type="bibr" rid="B16">16</xref>, <xref ref-type="bibr" rid="B26">26</xref>, <xref ref-type="bibr" rid="B27">27</xref>).</p>
<p>Constrictive haemodynamics is a term used to describe a specific form of physiologically significant haemodynamic compromise seen in pericardial constriction due to severe restriction of diastolic cardiac filling by the thickened and adhered pericardium (<xref ref-type="bibr" rid="B27">27</xref>). This is characterised by two important physiological principles: (1) dissociation of intrathoracic and intracardiac pressures, which drives respirophasic and reciprocal filling rates of the left and right ventricles, and (2) enhanced ventricular interaction due to respirophasic septal shift, which causes reciprocal ventricular filling of the left and right heart (<xref ref-type="bibr" rid="B27">27</xref>). These features are evident in pressure-volume haemodynamics and imaging modalities in patients with pericardial constriction (<xref ref-type="bibr" rid="B19">19</xref>). However, as seen in this case of ECP, the term &#x201C;constrictive haemodynamics&#x201D; does not specifically address the underlying pathophysiologic mechanism responsible for the increased pericardial stiffness leading to this impairment.</p>
<p>Echocardiography is widely regarded as the first-line investigation for the assessment of constrictive haemodynamics (<xref ref-type="bibr" rid="B25">25</xref>, <xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B29">29</xref>) and effectively demonstrates the principles of haemodynamic impairment through a combination of three echocardiographic measurements&#x2014;also commonly known as the Mayo Clinic Criteria. (1) Respirophasic ventricular septal shift is used as a sensitive inclusion marker (87&#x0025;) of constriction, whereafter a combination with either (2) medial e prime (e&#x2032;) &#x2265;9&#x2005;cm/s (indicating normal intrinsic myocardial relaxation ability) or (3) hepatic vein early expiratory diastolic wave flow reversal ratio &#x2265;0.79 is used to increase specificity to 91&#x0025; (<xref ref-type="bibr" rid="B18">18</xref>).</p>
<p>Also, strain evaluation using 2D speckle tracking has yielded promising results (<xref ref-type="bibr" rid="B30">30</xref>). It illustrates that pericardial tethering (pericardial attachment to the epicardial cardiac surface pulling on the myocardium) causes decreased peak systolic strain in free cardiac walls (adjacent to the adherent pericardium), while septal peak systolic strain is maintained&#x2014;the strain equivalent of annulus reversus seen on tissue Doppler. A left ventricular (LV) lateral wall to LV septal wall strain ratio of &#x003C;0.96 was shown to diagnose constrictive haemodynamics with a sensitivity of 89&#x0025; and a specificity of 96&#x0025; (<xref ref-type="bibr" rid="B30">30</xref>).</p>
<p>Although effective in demonstrating the constrictive haemodynamics seen in ECP, its inability to differentiate between the underlying mechanisms responsible for constrictive haemodynamics remains a significant limitation. Therefore, whether the constriction is related to a transient, reversible process or whether it is chronic and irreversible cannot be judged by looking at the presence or absence of constrictive haemodynamics alone.</p>
<p>CMR is currently described as a second-line investigation for evaluating pericardial disease (<xref ref-type="bibr" rid="B25">25</xref>, <xref ref-type="bibr" rid="B28">28</xref>). Apart from its ability to demonstrate constrictive haemodynamics with high sensitivity and specificity (<xref ref-type="bibr" rid="B22">22</xref>&#x2013;<xref ref-type="bibr" rid="B24">24</xref>), CMR can delineate potential surgical dissection planes pre-operatively (seen as epicardial and pericardial separation by epicardial fat of variable thickness) and contribute to the risk assessment plan prior to pericardiectomy (<xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B31">31</xref>). CMR&#x2019;s unique ability to quantify and stage pericarditis, based on the presence of the distinct processes of pericardial inflammation and oedema, sets it apart from other imaging modalities and enables us to unravel the complex mechanisms underpinning constrictive haemodynamics (<xref ref-type="bibr" rid="B16">16</xref>).</p>
<p>Pericardial inflammation results in neovascularisation, fibroblast proliferation, and expansion of the pericardial extravascular space, causing the otherwise relatively avascular pericardium to accumulate and retain gadolinium-based contrast agents, leading to increased signal on LGE imaging (<xref ref-type="bibr" rid="B32">32</xref>, <xref ref-type="bibr" rid="B33">33</xref>). Positron emission tomography (PET) data have shown this local pericardial inflammatory response to be especially intense in the case of TB pericarditis, where a pericardial inflammatory intensity [often quantified using the maximum standardised uptake value (SUVmax) on PET imaging] above a particular threshold was independently associated with a tuberculous aetiology (<xref ref-type="bibr" rid="B34">34</xref>).</p>
<p>Studies have also previously looked at the cytokine profile of this intense pericardial inflammatory response on a biochemical level, which demonstrated a pro-fibrotic inflammatory character dominated by high amounts of pro-inflammatory cytokines and low levels of anti-fibrotic N-acetyl-seryl-aspartyl-proline (Ac-SDKP) (<xref ref-type="bibr" rid="B35">35</xref>&#x2013;<xref ref-type="bibr" rid="B37">37</xref>). Specifically, interleukin-1 beta (IL-1B), tumour necrosis factor-alpha (TNF-&#x03B1;), and transforming growth factor-beta (TGF-&#x03B2;) are detectable in high quantities within TB pericardial effusions, and these have been closely associated with fibrosis in the setting of chronic inflammatory diseases, including TB (<xref ref-type="bibr" rid="B36">36</xref>, <xref ref-type="bibr" rid="B37">37</xref>).</p>
<p>Ac-SDKP is a naturally occurring immunomodulatory peptide hydrolysed from thymosin &#x03B2;4 by prolyl-oligopeptidase (POP) and is converted to its inactive peptides by angiotensin-converting enzyme (ACE) (<xref ref-type="bibr" rid="B7">7</xref>, <xref ref-type="bibr" rid="B35">35</xref>). It is hypothesised that Ac-SDKP serves a housekeeping function within the pericardium by inhibiting various major drivers of inflammation and fibrosis (see <xref ref-type="fig" rid="F3">Figure&#x00A0;3</xref>). These include the inhibition of the galectin-3-induced TGF-&#x03B2;/Smad2 signalling pathway, a direct inhibitory effect on TGF-&#x03B2;, and a direct blocking effect on collagen synthesis. Ac-SDKP is also thought to inhibit TNF-&#x03B1;, resulting in a subsequent reduction of macrophage and T-cell activation and lower levels of pro-inflammatory cytokines (see <xref ref-type="fig" rid="F3">Figure&#x00A0;3</xref>) (<xref ref-type="bibr" rid="B6">6</xref>&#x2013;<xref ref-type="bibr" rid="B8">8</xref>, <xref ref-type="bibr" rid="B35">35</xref>).</p>
<fig id="F3" position="float"><label>Figure 3</label>
<caption><p>Pericardial housekeeping function of Ac-SDKP regulates pericardial inflammation and fibrosis. The anti-inflammatory peptide Ac-SDKP downregulates pericardial inflammation and fibrosis through its inhibitory effects on: (1) the galectin-3 induced TGF-&#x03B2;/Smad2 signalling pathway and (2) downstream and direct inhibitory effects on TGF-&#x03B2;, collagen synthesis, and TNF-&#x03B1;. Ac-SDKP is converted to its inactive peptide by ACE, which may allow for a convenient therapeutic target to upregulate both local (pericardial) and systemic Ac-SDKP levels through ACE-inhibitor therapy.</p></caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="fcvm-11-1329767-g003.tif"/>
</fig>
<p>Furthermore, routinely available angiotensin-converting enzyme inhibitor (ACE-inhibitor) therapy was subsequently investigated and has proven effective in upregulating both local pericardial and systemic Ac-SDKP levels (<xref ref-type="bibr" rid="B7">7</xref>, <xref ref-type="bibr" rid="B8">8</xref>), with the potential to play a pivotal role in promoting anti-fibrotic activity to reduce pericardial inflammation, fibrosis, and eventual pericardial constriction. This clinical application is still unexplored in current TB pericarditis literature.</p>
<p>It remains unclear whether this pro-fibrotic nature of the inflammatory response itself, the high intensity of the pericardial inflammation seen in TB pericarditis, the prolonged duration of the pericardial inflammation (due to the chronicity of TB), or another feature of the TB pathology <italic>per se</italic> causally drives the high incidence of pericardial constriction following TB pericarditis (<xref ref-type="bibr" rid="B38">38</xref>).</p>
<p>Although CMR does not specifically capture the pro-fibrotic nature of the inflammatory response, the intensity of pericardial inflammation can be accurately detected and quantified by evaluating the pericardial signal intensity on LGE imaging, making this CMR sequence an important modality capable of demonstrating this substitute marker of pericardial inflammation (<xref ref-type="bibr" rid="B39">39</xref>). Using a greater intensity of pericardial inflammation (in isolation) as a prognostic marker for developing pericardial constriction has however yielded conflicting results. While it has effectively demonstrated a more favourable prognosis by expressing the contribution of active pericardial inflammation in constrictive haemodynamics, often associated with the acute reversible phase of pericarditis (<xref ref-type="bibr" rid="B14">14</xref>, <xref ref-type="bibr" rid="B15">15</xref>), it has also been associated with an increased risk of developing recurrent, chronic, and constrictive pericarditis (<xref ref-type="bibr" rid="B15">15</xref>, <xref ref-type="bibr" rid="B16">16</xref>, <xref ref-type="bibr" rid="B40">40</xref>&#x2013;<xref ref-type="bibr" rid="B42">42</xref>).</p>
<p>Based on a study correlating CMR signals with histology, it has recently been suggested that a combination of pericardial inflammation and oedema signifies CMR evidence of acute pericarditis (<xref ref-type="bibr" rid="B16">16</xref>). In contrast, the absence of these two features defines a state of inert, burnt-out pericarditis (<xref ref-type="bibr" rid="B16">16</xref>). Between these extremes lie sub-acute and chronic pericarditis. Although both sub-acute and chronic pericarditis are associated with variable quantities of pericardial inflammation, sub-acute pericarditis is characterised by patchy areas of residual pericardial oedema, whereas chronic pericarditis is distinguished by the absence of residual pericardial oedema (<xref ref-type="bibr" rid="B16">16</xref>). Therefore, CMR can be used not only to quantify pericardial inflammation but also to stage the chronicity of disease by combining an analysis of inflammation (LGE) with that of oedema (T2-STIR and T2 mapping) (<xref ref-type="bibr" rid="B16">16</xref>). T2-STIR sequences, as well as T2-weighted mapping, are highly specific for detecting increased water content in tissues and can therefore identify pericardial oedema, a marker of acuteness and reversibility of pericarditis and potentially its complications, particularly when seen in the setting of residual pericardial inflammation (<xref ref-type="bibr" rid="B16">16</xref>).</p>
<p>In contrast with idiopathic pericarditis (<xref ref-type="bibr" rid="B39">39</xref>), TB pericarditis may display a prominent chronic pericarditis phase (absent pericardial oedema), combined with high-intensity residual pericardial inflammation, as illustrated in the following case.</p>
</sec>
</sec>
<sec id="s3"><title>Case 2</title>
<p>A 26-year-old HIV-uninfected man presented with constitutional symptoms, exertional dyspnoea, and a clinical examination suggestive of a pericardial effusion. TTE confirmed a large, circumferential pericardial effusion conducive to pericardiocentesis, which was subsequently performed and confirmed a diagnosis of rifampicin-sensitive, definite TB pericarditis (<xref ref-type="bibr" rid="B17">17</xref>). This case was classified as ECP, as evidenced by the persistence of constrictive haemodynamics following successful pericardiocentesis (<xref ref-type="bibr" rid="B19">19</xref>).</p>
<p>A CMR was performed 6 days after the initial pericardiocentesis (baseline study), which revealed a large re-accumulated circumferential pericardial effusion. The CMR further illustrated intense residual pericardial inflammation on LGE sequences (see <xref ref-type="fig" rid="F4">Figure&#x00A0;4A</xref>) but no associated acute pericardial oedema on T2-weighted STIR or T2 mapping sequences (see <xref ref-type="fig" rid="F4">Figures&#x00A0;4B,C</xref>).</p>
<fig id="F4" position="float"><label>Figure 4</label>
<caption><p>Case 2: Baseline CMR findings&#x2014;chronic TB pericarditis with intense residual pericardial inflammation and a large recurrent pericardial effusion. (<bold>A</bold>) LGE image showing hyperintense circumferential pericardial signal indicative of intense circumferential pericardial inflammation. (<bold>B</bold>) T2-STIR and (<bold>C</bold>) T2 mapping images showing normal pericardial signal intensities indicative of absent pericardial oedema. The combination of (1) intense pericardial inflammation in the setting of (2) chronic pericarditis (absent pericardial oedema) likely represents the highest cumulative risk of developing constrictive pericarditis. Despite the visceral and parietal pericardium being separated by a large pericardial effusion, the pro-fibrotic &#x201C;sticky&#x201D; visceral and parietal pericardium is in the process of tissue remodelling and has a high risk of becoming adherent as the residual pericardial effusion resorbs. Compressive effects from the residual pericardial effusion still contribute to reversible constrictive haemodynamics; therefore, medical therapy needs to be continued until the pericardial fluid has completely resorbed.</p></caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="fcvm-11-1329767-g004.tif"/>
</fig>
<p>The patient was initiated on the local first-line anti-tuberculous chemotherapy regime (<xref ref-type="bibr" rid="B20">20</xref>) without adjunctive anti-inflammatory medication and was followed up at a primary healthcare facility. Around the time of completing his anti-tuberculous chemotherapy (6 months after treatment initiation), the patient was noted to have developed progressive signs of predominantly right-sided cardiac failure. Due to poor access to transport and a congested medical service in a resource-limited setting, specialist follow-up was delayed, and the patient was only seen at a cardiology service 3 months later. At this stage, the TTE confirmed constrictive haemodynamics, and a repeat CMR study demonstrated complete resolution of the prior intense pericardial inflammation observed on LGE imaging (see <xref ref-type="fig" rid="F5">Figure&#x00A0;5A</xref>). No associated pericardial oedema was present on either T2-STIR or T2 mapping sequences (see <xref ref-type="fig" rid="F5">Figures&#x00A0;5B,C</xref>), suggesting that a burnt-out pericardial constriction phase was entered with little to no expectation of spontaneous resolution of the pericardial constriction.</p>
<fig id="F5" position="float"><label>Figure 5</label>
<caption><p>Case 2: 9-month follow-up CMR findings&#x2014;burnt-out TB pericarditis. (<bold>A</bold>) LGE image showing the absence of a pericardial signal, demonstrating complete resolution of pericardial inflammation. (<bold>B</bold>) T2-STIR and (<bold>C</bold>) T2 mapping images showing normal pericardial signal intensities, demonstrating the absence of pericardial oedema. A burnt-out (resolved pericardial inflammation and oedema) CMR picture of TB pericarditis in the setting of constrictive haemodynamics is an indication for pericardiectomy.</p></caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="fcvm-11-1329767-g005.tif"/>
</fig>
<p>The patient was subsequently referred for early pericardiectomy, which confirmed constrictive pericarditis with organised fibrosis of the pericardium demonstrated on histology.</p>
<sec id="s3a"><title>Case 2: discussion</title>
<p>Employing CMR to stage and quantify pericardial inflammation could potentially assist not only in prognosticating patients at higher risk of tissue remodelling and pericardial constriction but also in predicting the degree of disease reversibility, tailoring medical therapy, and determining the ideal timing for surgical pericardiectomy (<xref ref-type="bibr" rid="B9">9</xref>&#x2013;<xref ref-type="bibr" rid="B16">16</xref>).</p>
<p>When choosing the most appropriate therapy, the stage of pericardial inflammation (as indicated by the presence of residual pericardial oedema on T2-STIR and T2 mapping) could be used to predict the reversibility of constrictive haemodynamics, while the intensity of pericardial inflammation (as quantified on LGE sequences) could be used to predict risk for continued pericardial tissue remodelling and fibrosis (see <xref ref-type="fig" rid="F6">Figure&#x00A0;6</xref>) (<xref ref-type="bibr" rid="B14">14</xref>&#x2013;<xref ref-type="bibr" rid="B16">16</xref>).</p>
<fig id="F6" position="float"><label>Figure 6</label>
<caption><p>CMR-based model to predict constrictive pericarditis risk&#x2014;a product of pericardial inflammation and oedema.</p></caption>
<graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="fcvm-11-1329767-g006.tif"/>
</fig>
<p>Staging pericarditis offers a potentially elegant solution to the previously mentioned discrepant findings seen in the CMR-derived pericardial inflammatory signal to predict constriction risk. Based on this staging model, oedema (T2-STIR and T2 signal) tracks acuteness, whereas inflammation (LGE signal), although typically present in the acute phase, can also extend into the sub-acute and chronic phases (<xref ref-type="bibr" rid="B16">16</xref>). Therefore, an analysis of the stage of pericarditis may be required in conjunction with the inflammatory intensity to contextualise the inflammation and subsequent constriction risk (see <xref ref-type="fig" rid="F6">Figure&#x00A0;6</xref>).</p>
<p>The current best evidence suggests that, in acute pericarditis, an acute inflammatory response combined with pericardial oedema causes the pericardium to stiffen and become less compliant (<xref ref-type="bibr" rid="B16">16</xref>). Depending on the intensity and distribution of inflammation and oedema, this initial inflammatory response can result in decreased pericardial compliance and transient constrictive haemodynamics (<xref ref-type="bibr" rid="B16">16</xref>). However, even though the acute stage is transient and typically reversible, the intensity of inflammation seen in this stage may predict the future risk of dysfunctional, fibrotic healing and persistent constrictive haemodynamics, i.e., chronic CP (<xref ref-type="bibr" rid="B15">15</xref>).</p>
<p>In sub-acute pericarditis, oedema is seen to have resolved in some, but not all, pericardial segments, leaving patchy areas of the T2 signal where oedema persists and actively contribute to constrictive haemodynamics (<xref ref-type="bibr" rid="B16">16</xref>). Areas with residual inflammation but resolved oedema are thought to represent a stage in the process of healing, which can occur either with or without the formation of visceral&#x2013;parietal adhesion&#x2014;once again, the risk of healing with fibrosis is likely dependent on the intensity of the initial inflammatory response during the acute stage of the disease (<xref ref-type="bibr" rid="B15">15</xref>, <xref ref-type="bibr" rid="B16">16</xref>).</p>
<p>Finally, in chronic pericarditis, inflammation of varying intensity may persist, along with the potential for ongoing tissue remodelling and fibrosis. Oedema is observed to have completely resolved; therefore, areas with established pericardial fibrosis are permanent and irreversible (<xref ref-type="bibr" rid="B16">16</xref>). In this chronic stage of the disease, if constrictive haemodynamics is present, it is likely to be irreversible, and pericardiectomy is indicated.</p>
</sec>
</sec>
<sec id="s4"><title>Constrictive haemodynamics&#x2014;an added prognostic opportunity?</title>
<p>The permanence of constrictive haemodynamics needs to be assessed within the context of its associated pericardial inflammation (on LGE imaging) and oedema (T2-STIR or T2 mapping), i.e., stage of the pericarditis (<xref ref-type="bibr" rid="B16">16</xref>). While constrictive haemodynamics might be transient and reversible in acute pericarditis, the presence of constrictive haemodynamics in sub-acute and chronic pericarditis represents two points on the spectrum of ECP, where the relative contribution from acute (and subsequently reversible) constrictive haemodynamics becomes sequentially smaller, while the contribution from established pericardial scarring (and subsequently non-reversible constrictive haemodynamics) becomes progressively larger (<xref ref-type="bibr" rid="B16">16</xref>). Therefore, the presence of constrictive physiology at any stage of the disease, particularly in later stages, is likely a sign of increased pericardial fibrosis burden and represents a state of impaired physiological diastolic reserve brought about by established pericardial scarring, even in the absence of a final constrictive outcome. However, the sooner a patient transitions from constrictive to non-constrictive haemodynamics, i.e., transitions in the acute rather than the sub-acute stage, the less significant the limitation of their final physiological diastolic reserve is likely to be.</p>
</sec>
<sec id="s5"><title>T2-weighted STIR&#x2014;an indicator of reversibility or merely a marker of chronicity?</title>
<p>The reversibility of constrictive haemodynamics, as assessed by both (1) the intensity of pericardial inflammation (LGE imaging) and (2) pericardial oedema (on T2-STIR and T2 mapping), remains poorly explored. Prior studies that evaluated the contribution of active pericardial inflammation in constrictive physiology were conducted in the &#x201C;pre-staging&#x201D; era of pericarditis (<xref ref-type="bibr" rid="B14">14</xref>, <xref ref-type="bibr" rid="B15">15</xref>). Notably, these studies only evaluated the contribution of LGE, a significant methodological limitation that may now be overcome in the era of multi-parametric CMR that includes oedema imaging and T2 mapping. Although one would expect a relatively linear relationship between an intensely inflamed pericardium and pericardial oedema and that oedema would resolve as the intensity of inflammation subsides, a clear disconnect between inflammatory and oedema signals is commonly observed in the context of TB pericarditis. This then begs the question of whether residual pericardial inflammation, in the absence of associated oedema (chronic pericarditis), represents residual reversible haemodynamics. Further research utilising multi-modal CMR in regions with a high burden of TB is clearly required.</p>
</sec>
<sec id="s6" sec-type="conclusions"><title>Conclusion</title>
<p>Although there remains uncertainty regarding the relative contribution of isolated pericardial inflammation (the absence of oedema) to reversible constrictive haemodynamics, there is no doubt that CMR may add significant diagnostic value in complex clinical cases of pericarditis. This becomes especially relevant in low- to middle-income settings like sub-Saharan Africa, where TB pericarditis is prevalent and carries a high inherent risk of progression to pericardial constriction. Further studies are required to explore the relative contributions of pericardial inflammation and oedema as mutually non-exclusive entities (may co-exist without clear linearity), contributing to the final constrictive risk. The apparent disconnect between marked residual pericardial inflammation in the setting of chronic TB pericarditis (in the absence of pericardial oedema) needs to be further researched to determine its role as a potential catalyst underpinning the disproportionately high risk of constrictive pericarditis observed in individuals with TB pericarditis.</p>
</sec>
</body>
<back>
<sec id="s7" sec-type="author-contributions"><title>Author contributions</title>
<p>LG: Writing &#x2013; original draft, Writing &#x2013; review &#x0026; editing. AD: Supervision, Writing &#x2013; review &#x0026; editing. PR: Writing &#x2013; review &#x0026; editing. TJ: Writing &#x2013; review &#x0026; editing. PH: Supervision, Writing &#x2013; review &#x0026; editing.</p>
</sec>
<sec id="s8" sec-type="funding-information"><title>Funding</title>
<p>The authors declare that no financial support was received for the research, authorship, and/or publication of this article.</p>
</sec>
<sec id="s9" sec-type="COI-statement"><title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s10" sec-type="disclaimer"><title>Publisher&#x0027;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<ref-list><title>References</title>
<ref id="B1"><label>1.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rodriguez</surname><given-names>ER</given-names></name><name><surname>Tan</surname><given-names>CD</given-names></name></person-group>. <article-title>Structure and anatomy of the human pericardium</article-title>. <source>Prog Cardiovasc Dis</source>. (<year>2017</year>) <volume>59</volume>:<fpage>327</fpage>&#x2013;<lpage>40</lpage>. <pub-id pub-id-type="doi">10.1016/j.pcad.2016.12.010</pub-id><pub-id pub-id-type="pmid">28062264</pub-id></citation></ref>
<ref id="B2"><label>2.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Reuter</surname><given-names>H</given-names></name><name><surname>Burgess</surname><given-names>LJ</given-names></name><name><surname>Doubell</surname><given-names>AF</given-names></name></person-group>. <article-title>Epidemiology of pericardial effusions at a large academic hospital in South Africa</article-title>. <source>Epidemiol Infect</source>. (<year>2005</year>) <volume>133</volume>:<fpage>393</fpage>&#x2013;<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1017/S0950268804003577</pub-id><pub-id pub-id-type="pmid">15962545</pub-id></citation></ref>
<ref id="B3"><label>3.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mayosi</surname><given-names>BM</given-names></name></person-group>. <article-title>Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in sub-Saharan Africa</article-title>. <source>Heart</source>. (<year>2007</year>) <volume>93</volume>:<fpage>1176</fpage>&#x2013;<lpage>83</lpage>. <pub-id pub-id-type="doi">10.1136/hrt.2007.127746</pub-id><pub-id pub-id-type="pmid">17890693</pub-id></citation></ref>
<ref id="B4"><label>4.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>L&#x00F3;pez-L&#x00F3;pez</surname><given-names>JP</given-names></name><name><surname>Posada-Mart&#x00ED;nez</surname><given-names>EL</given-names></name><name><surname>Saldarriaga</surname><given-names>C</given-names></name><name><surname>Wyss</surname><given-names>F</given-names></name><name><surname>Ponte-Negretti</surname><given-names>CI</given-names></name><name><surname>Alexander</surname><given-names>B</given-names></name><etal/></person-group> <article-title>Tuberculosis and the heart</article-title>. <source>J Am Heart Assoc</source>. (<year>2021</year>) <volume>10</volume>:<fpage>7</fpage>. <pub-id pub-id-type="doi">10.1161/jaha.120.019435</pub-id></citation></ref>
<ref id="B5"><label>5.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Adefuye</surname><given-names>MA</given-names></name><name><surname>Manjunatha</surname><given-names>N</given-names></name><name><surname>Ganduri</surname><given-names>V</given-names></name><name><surname>Rajasekaran</surname><given-names>K</given-names></name><name><surname>Duraiyarasan</surname><given-names>S</given-names></name><name><surname>Adefuye</surname><given-names>BO</given-names></name></person-group>. <article-title>Tuberculosis and cardiovascular complications: an overview</article-title>. <source>Cureus</source>. (<year>2022</year>) <volume>14</volume>:<fpage>8</fpage>. <pub-id pub-id-type="doi">10.7759/cureus.28268</pub-id></citation></ref>
<ref id="B6"><label>6.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ramasamy</surname><given-names>V</given-names></name><name><surname>Mayosi</surname><given-names>BM</given-names></name><name><surname>Sturrock</surname><given-names>ED</given-names></name><name><surname>Ntsekhe</surname><given-names>M</given-names></name></person-group>. <article-title>Established and novel pathophysiological mechanisms of pericardial injury and constrictive pericarditis</article-title>. <source>World J Cardiol</source>. (<year>2018</year>) <volume>10</volume>:<fpage>87</fpage>&#x2013;<lpage>96</lpage>. <pub-id pub-id-type="doi">10.4330/wjc.v10.i9.87</pub-id><pub-id pub-id-type="pmid">30344956</pub-id></citation></ref>
<ref id="B7"><label>7.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kumar</surname><given-names>N</given-names></name><name><surname>Yin</surname><given-names>C</given-names></name></person-group>. <article-title>The anti-inflammatory peptide Ac-SDKP: synthesis, role in ACE inhibition, and its therapeutic potential in hypertension and cardiovascular diseases</article-title>. <source>Pharmacol Res</source>. (<year>2018</year>) <volume>134</volume>:<fpage>268</fpage>&#x2013;<lpage>79</lpage>. <pub-id pub-id-type="doi">10.1016/j.phrs.2018.07.006</pub-id><pub-id pub-id-type="pmid">29990624</pub-id></citation></ref>
<ref id="B8"><label>8.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Naicker</surname><given-names>K</given-names></name><name><surname>Ntsekhe</surname><given-names>M</given-names></name></person-group>. <article-title>Tuberculous pericardial disease: a focused update on diagnosis, therapy and prevention of complications</article-title>. <source>Cardiovasc Diagn Ther</source>. (<year>2020</year>) <volume>10</volume>:<fpage>289</fpage>&#x2013;<lpage>95</lpage>. <pub-id pub-id-type="doi">10.21037/cdt.2019.09.20</pub-id><pub-id pub-id-type="pmid">32420111</pub-id></citation></ref>
<ref id="B9"><label>9.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yadav</surname><given-names>S</given-names></name><name><surname>Shah</surname><given-names>S</given-names></name><name><surname>Iqbal</surname><given-names>Z</given-names></name><name><surname>Alharbi</surname><given-names>MG</given-names></name><name><surname>Kalra</surname><given-names>HS</given-names></name><name><surname>Suri</surname><given-names>M</given-names></name><etal/></person-group> <article-title>Pericardiectomy for constrictive tuberculous pericarditis: a systematic review and meta-analysis on the etiology, patients&#x2019; characteristics, and the outcomes</article-title>. <source>Cureus</source>. (<year>2021</year>) <volume>13</volume>:<fpage>9</fpage>. <pub-id pub-id-type="doi">10.7759/cureus.18252</pub-id></citation></ref>
<ref id="B10"><label>10.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Brijmohan Bhattad</surname><given-names>P</given-names></name><name><surname>Jain</surname><given-names>V</given-names></name><name><surname>Quillen</surname><given-names>JH</given-names></name></person-group>. <article-title>Constrictive pericarditis: a commonly missed cause of treatable diastolic heart failure</article-title>. <source>Cureus</source>. (<year>2020</year>) <volume>12</volume>:<fpage>5</fpage>. <pub-id pub-id-type="doi">10.7759/cureus.8024</pub-id></citation></ref>
<ref id="B11"><label>11.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gopaldas</surname><given-names>RR</given-names></name><name><surname>Dao</surname><given-names>TK</given-names></name><name><surname>Caron</surname><given-names>NR</given-names></name><name><surname>Markley</surname><given-names>JG</given-names></name></person-group>. <article-title>Predictors of in-hospital complications after pericardiectomy: a nationwide outcomes study</article-title>. <source>J Thorac Cardiovasc Surg</source>. (<year>2013</year>) <volume>145</volume>:<fpage>1227</fpage>&#x2013;<lpage>33</lpage>. <pub-id pub-id-type="doi">10.1016/j.jtcvs.2012.03.072</pub-id><pub-id pub-id-type="pmid">22578895</pub-id></citation></ref>
<ref id="B12"><label>12.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Busch</surname><given-names>C</given-names></name><name><surname>Penov</surname><given-names>K</given-names></name><name><surname>Amorim</surname><given-names>PA</given-names></name><name><surname>Garbade</surname><given-names>J</given-names></name><name><surname>Davierwala</surname><given-names>P</given-names></name><name><surname>Schuler</surname><given-names>GC</given-names></name><etal/></person-group> <article-title>Risk factors for mortality after pericardiectomy for chronic constrictive pericarditis in a large single-centre cohort</article-title>. <source>Eur J Cardiothorac Surg</source>. (<year>2015</year>) <volume>48</volume>:<fpage>110</fpage>&#x2013;<lpage>6</lpage>. <pub-id pub-id-type="doi">10.1093/ejcts/ezv322</pub-id></citation></ref>
<ref id="B13"><label>13.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bozbuga</surname><given-names>N</given-names></name><name><surname>Erentug</surname><given-names>V</given-names></name><name><surname>Eren</surname><given-names>E</given-names></name><name><surname>Erdogan</surname><given-names>HB</given-names></name><name><surname>Kirali</surname><given-names>K</given-names></name><name><surname>Antal</surname><given-names>A</given-names></name><etal/></person-group> <article-title>Pericardiectomy for chronic constrictive tuberculous pericarditis: risks and predictors of survival</article-title>. <source>Tex Heart Inst J</source>. (<year>2003</year>) <volume>30</volume>:<fpage>180</fpage>&#x2013;<lpage>5</lpage>.<pub-id pub-id-type="pmid">12959199</pub-id></citation></ref>
<ref id="B14"><label>14.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Feng</surname><given-names>D</given-names></name><name><surname>Glockner</surname><given-names>J</given-names></name><name><surname>Kim</surname><given-names>K</given-names></name><name><surname>Martinez</surname><given-names>M</given-names></name><name><surname>Syed</surname><given-names>IS</given-names></name><name><surname>Araoz</surname><given-names>P</given-names></name><etal/></person-group> <article-title>Cardiac magnetic resonance imaging pericardial late gadolinium enhancement and elevated inflammatory markers can predict the reversibility of constrictive pericarditis after anti-inflammatory medical therapy: a pilot study</article-title>. <source>Circulation</source>. (<year>2011</year>) <volume>124</volume>:<fpage>1830</fpage>&#x2013;<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCULATIONAHA.111.026070</pub-id><pub-id pub-id-type="pmid">21969014</pub-id></citation></ref>
<ref id="B15"><label>15.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cremer</surname><given-names>PC</given-names></name><name><surname>Tariq</surname><given-names>MU</given-names></name><name><surname>Karwa</surname><given-names>A</given-names></name><name><surname>Alraies</surname><given-names>MC</given-names></name><name><surname>Benatti</surname><given-names>R</given-names></name><name><surname>Schuster</surname><given-names>A</given-names></name><etal/></person-group> <article-title>Quantitative assessment of pericardial delayed hyperenhancement predicts clinical improvement in patients with constrictive pericarditis treated with anti-inflammatory therapy</article-title>. <source>Circ Cardiovasc Imaging</source>. (<year>2015</year>) <volume>8</volume>:<fpage>5</fpage>. <pub-id pub-id-type="doi">10.1161/circimaging.114.003125</pub-id></citation></ref>
<ref id="B16"><label>16.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chetrit</surname><given-names>M</given-names></name><name><surname>Xu</surname><given-names>B</given-names></name><name><surname>Kwon</surname><given-names>DH</given-names></name><name><surname>Ramchand</surname><given-names>J</given-names></name><name><surname>Rodriguez</surname><given-names>RE</given-names></name><name><surname>Tan</surname><given-names>CD</given-names></name><etal/></person-group> <article-title>Imaging-guided therapies for pericardial diseases</article-title>. <source>JACC Cardiovasc Imaging</source>. (<year>2020</year>) <volume>13</volume>:<fpage>1422</fpage>&#x2013;<lpage>37</lpage>. <pub-id pub-id-type="doi">10.1016/j.jcmg.2019.08.027</pub-id><pub-id pub-id-type="pmid">31734199</pub-id></citation></ref>
<ref id="B17"><label>17.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Reuter</surname><given-names>H</given-names></name><name><surname>Burgess</surname><given-names>L</given-names></name><name><surname>van Vuuren</surname><given-names>W</given-names></name><name><surname>Doubell</surname><given-names>A</given-names></name></person-group>. <article-title>Diagnosing tuberculous pericarditis</article-title>. <source>QJM</source>. (<year>2006</year>) <volume>99</volume>:<fpage>827</fpage>&#x2013;<lpage>39</lpage>. <pub-id pub-id-type="doi">10.1093/qjmed/hcl123</pub-id><pub-id pub-id-type="pmid">17121764</pub-id></citation></ref>
<ref id="B18"><label>18.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Welch</surname><given-names>TD</given-names></name><name><surname>Ling</surname><given-names>LH</given-names></name><name><surname>Espinosa</surname><given-names>RE</given-names></name><name><surname>Anavekar</surname><given-names>NS</given-names></name><name><surname>Wiste</surname><given-names>HJ</given-names></name><name><surname>Lahr</surname><given-names>BD</given-names></name><etal/></person-group> <article-title>Echocardiographic diagnosis of constrictive pericarditis: Mayo Clinic criteria</article-title>. <source>Circ Cardiovasc Imaging</source>. (<year>2014</year>) <volume>7</volume>:<fpage>526</fpage>&#x2013;<lpage>34</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCIMAGING.113.001613</pub-id><pub-id pub-id-type="pmid">24633783</pub-id></citation></ref>
<ref id="B19"><label>19.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>van der Bijl</surname><given-names>P</given-names></name><name><surname>Herbst</surname><given-names>P</given-names></name><name><surname>Doubell</surname><given-names>AF</given-names></name></person-group>. <article-title>Redefining effusive-constrictive pericarditis with echocardiography</article-title>. <source>J Cardiovasc Ultrasound</source>. (<year>2016</year>) <volume>24</volume>:<fpage>317</fpage>&#x2013;<lpage>23</lpage>. <pub-id pub-id-type="doi">10.4250/jcu.2016.24.4.317</pub-id><pub-id pub-id-type="pmid">28090260</pub-id></citation></ref>
<ref id="B20"><label>20.</label><citation citation-type="other"><article-title>National Tuberculosis Management Guidelines, Department of Health Knowledge (2014)</article-title>. <comment>Available online at:</comment> <ext-link ext-link-type="uri" xlink:href="https://knowledgehub.health.gov.za/system/files/elibdownloads/2023-04/National%252520TB%252520management%252520guidelines%2525202014.pdf">https://knowledgehub.health.gov.za/system/files/elibdownloads/2023-04/National&#x0025;252520TB&#x0025;252520management&#x0025;252520guidelines&#x0025;2525202014.pdf</ext-link> <comment>(accessed October 15, 2023)</comment>.</citation></ref>
<ref id="B21"><label>21.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Oh</surname><given-names>JK</given-names></name><name><surname>Hatle</surname><given-names>LK</given-names></name><name><surname>Seward</surname><given-names>JB</given-names></name><name><surname>Danielson</surname><given-names>GK</given-names></name><name><surname>Schaff</surname><given-names>HV</given-names></name><name><surname>Reeder</surname><given-names>GS</given-names></name><etal/></person-group> <article-title>Diagnostic role of Doppler echocardiography in constrictive pericarditis</article-title>. <source>J Am Coll Cardiol</source>. (<year>1994</year>) <volume>23</volume>:<fpage>154</fpage>&#x2013;<lpage>62</lpage>. <pub-id pub-id-type="doi">10.1016/0735-1097(94)90514-2</pub-id><pub-id pub-id-type="pmid">8277074</pub-id></citation></ref>
<ref id="B22"><label>22.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Francone</surname><given-names>M</given-names></name><name><surname>Dymarkowski</surname><given-names>S</given-names></name><name><surname>Kalantzi</surname><given-names>M</given-names></name><name><surname>Rademakers</surname><given-names>FE</given-names></name><name><surname>Bogaert</surname><given-names>J</given-names></name></person-group>. <article-title>Assessment of ventricular coupling with real-time cine MRI and its value to differentiate constrictive pericarditis from restrictive cardiomyopathy</article-title>. <source>Eur Radiol</source>. (<year>2006</year>) <volume>16</volume>:<fpage>944</fpage>&#x2013;<lpage>51</lpage>. <pub-id pub-id-type="doi">10.1007/s00330-005-0009-0</pub-id><pub-id pub-id-type="pmid">16228208</pub-id></citation></ref>
<ref id="B23"><label>23.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Anavekar</surname><given-names>NS</given-names></name><name><surname>Wong</surname><given-names>BF</given-names></name><name><surname>Foley</surname><given-names>TA</given-names></name><name><surname>Bishu</surname><given-names>K</given-names></name><name><surname>Kolipaka</surname><given-names>A</given-names></name><name><surname>Koo</surname><given-names>CW</given-names></name><etal/></person-group> <article-title>Index of biventricular interdependence calculated using cardiac MRI: a proof of concept study in patients with and without constrictive pericarditis</article-title>. <source>Int J Cardiovasc Imaging</source>. (<year>2013</year>) <volume>29</volume>:<fpage>363</fpage>&#x2013;<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1007/s10554-012-0101-x</pub-id><pub-id pub-id-type="pmid">22821473</pub-id></citation></ref>
<ref id="B24"><label>24.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Thavendiranathan</surname><given-names>P</given-names></name><name><surname>Verhaert</surname><given-names>D</given-names></name><name><surname>Walls</surname><given-names>MC</given-names></name><name><surname>Bender</surname><given-names>JA</given-names></name><name><surname>Rajagopalan</surname><given-names>S</given-names></name><name><surname>Chung</surname><given-names>YC</given-names></name><etal/></person-group> <article-title>Simultaneous right and left heart real-time, free-breathing CMR flow quantification identifies constrictive physiology</article-title>. <source>JACC Cardiovasc Imaging</source>. (<year>2012</year>) <volume>5</volume>:<fpage>15</fpage>&#x2013;<lpage>24</lpage>. <pub-id pub-id-type="doi">10.1016/j.jcmg.2011.07.010</pub-id><pub-id pub-id-type="pmid">22239888</pub-id></citation></ref>
<ref id="B25"><label>25.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Adler</surname><given-names>Y</given-names></name><name><surname>Charron</surname><given-names>P</given-names></name><name><surname>Imazio</surname><given-names>M</given-names></name><name><surname>Badano</surname><given-names>L</given-names></name><name><surname>Bar&#x00F3;n-Esquivias</surname><given-names>G</given-names></name><name><surname>Bogaert</surname><given-names>J</given-names></name><etal/></person-group> <article-title>2015 ESC guidelines for the diagnosis and management of pericardial diseases</article-title>. <source>Eur Heart J</source>. (<year>2015</year>) <volume>36</volume>:<fpage>2921</fpage>&#x2013;<lpage>64</lpage>. <pub-id pub-id-type="doi">10.1093/eurheartj/ehv318</pub-id><pub-id pub-id-type="pmid">26320112</pub-id></citation></ref>
<ref id="B26"><label>26.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Syed</surname><given-names>FF</given-names></name><name><surname>Ntsekhe</surname><given-names>M</given-names></name><name><surname>Mayosi</surname><given-names>BM</given-names></name><name><surname>Oh</surname><given-names>JK</given-names></name></person-group>. <article-title>Effusive-constrictive pericarditis</article-title>. <source>Heart Fail Rev</source>. (<year>2013</year>) <volume>18</volume>:<fpage>277</fpage>&#x2013;<lpage>87</lpage>. <pub-id pub-id-type="doi">10.1007/s10741-012-9308-0</pub-id><pub-id pub-id-type="pmid">22422296</pub-id></citation></ref>
<ref id="B27"><label>27.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kyriakakis</surname><given-names>C</given-names></name><name><surname>Herbst</surname><given-names>P</given-names></name><name><surname>Doubell</surname><given-names>A</given-names></name></person-group>. <article-title>Constrictive pericarditis&#x2014;prevalence, causes and clinical presentation</article-title>. <source>E-J Cardiol Pract</source>. (<year>2017</year>) <volume>15</volume>:<fpage>22</fpage>. <comment>Available online at:</comment> <ext-link ext-link-type="uri" xlink:href="https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-15/Constrictive-pericarditis-prevalence-causes-and-clinical-presentation">https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-15/Constrictive-pericarditis-prevalence-causes-and-clinical-presentation</ext-link> <comment>(accessed May 28, 2023)</comment>.</citation></ref>
<ref id="B28"><label>28.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cosyns</surname><given-names>B</given-names></name><name><surname>Plein</surname><given-names>S</given-names></name><name><surname>Nihoyanopoulos</surname><given-names>P</given-names></name><name><surname>Smiseth</surname><given-names>O</given-names></name><name><surname>Achenbach</surname><given-names>S</given-names></name><name><surname>Andrade</surname><given-names>MJ</given-names></name><etal/></person-group> <article-title>European association of cardiovascular imaging (EACVI) position paper: multimodality imaging in pericardial disease</article-title>. <source>Eur Heart J Cardiovasc Imaging</source>. (<year>2015</year>) <volume>16</volume>:<fpage>12</fpage>&#x2013;<lpage>31</lpage>. <pub-id pub-id-type="doi">10.1093/ehjci/jeu128</pub-id><pub-id pub-id-type="pmid">25248336</pub-id></citation></ref>
<ref id="B29"><label>29.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Alajaji</surname><given-names>W</given-names></name><name><surname>Xu</surname><given-names>B</given-names></name><name><surname>Sripariwuth</surname><given-names>A</given-names></name><name><surname>Menon</surname><given-names>V</given-names></name><name><surname>Kumar</surname><given-names>A</given-names></name><name><surname>Schleicher</surname><given-names>M</given-names></name><etal/></person-group> <article-title>Noninvasive multimodality imaging for the diagnosis of constrictive pericarditis</article-title>. <source>Circ Cardiovasc Imaging</source>. (<year>2018</year>) <volume>11</volume>:<fpage>11</fpage>. <pub-id pub-id-type="doi">10.1161/circimaging.118.007878</pub-id></citation></ref>
<ref id="B30"><label>30.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kusunose</surname><given-names>K</given-names></name><name><surname>Dahiya</surname><given-names>A</given-names></name><name><surname>Popovi&#x0107;</surname><given-names>ZB</given-names></name><name><surname>Motoki</surname><given-names>H</given-names></name><name><surname>Alraies</surname><given-names>MC</given-names></name><name><surname>Zurick</surname><given-names>AO</given-names></name><etal/></person-group> <article-title>Biventricular mechanics in constrictive pericarditis comparison with restrictive cardiomyopathy and impact of pericardiectomy</article-title>. <source>Circ Cardiovasc Imaging</source>. (<year>2013</year>) <volume>6</volume>:<fpage>399</fpage>&#x2013;<lpage>406</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCIMAGING.112.000078</pub-id><pub-id pub-id-type="pmid">23532508</pub-id></citation></ref>
<ref id="B31"><label>31.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rienm&#x00FC;ller</surname><given-names>R</given-names></name><name><surname>G&#x00FC;rgan</surname><given-names>M</given-names></name><name><surname>Erdmann</surname><given-names>E</given-names></name><name><surname>Kemkes</surname><given-names>BM</given-names></name><name><surname>Kreutzer</surname><given-names>E</given-names></name><name><surname>Weinhold</surname><given-names>C</given-names></name></person-group>. <article-title>CT And MR evaluation of pericardial constriction: a new diagnostic and therapeutic concept</article-title>. <source>J Thorac Imaging</source>. (<year>1993</year>) <volume>8</volume>:<fpage>108</fpage>&#x2013;<lpage>21</lpage>. <pub-id pub-id-type="doi">10.1097/00005382-199321000-00004</pub-id></citation></ref>
<ref id="B32"><label>32.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Xu</surname><given-names>B</given-names></name><name><surname>Harb</surname><given-names>SC</given-names></name><name><surname>Klein</surname><given-names>AL</given-names></name></person-group>. <article-title>Utility of multimodality cardiac imaging in disorders of the pericardium</article-title>. <source>Echo Res Pract</source>. (<year>2018</year>) <volume>5</volume>:<fpage>37</fpage>&#x2013;<lpage>48</lpage>. <pub-id pub-id-type="doi">10.1530/ERP-18-0019</pub-id></citation></ref>
<ref id="B33"><label>33.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zurick</surname><given-names>AO</given-names></name><name><surname>Bolen</surname><given-names>MA</given-names></name><name><surname>Kwon</surname><given-names>DH</given-names></name><name><surname>Tan</surname><given-names>CD</given-names></name><name><surname>Popovic</surname><given-names>ZB</given-names></name><name><surname>Rajeswaran</surname><given-names>J</given-names></name><etal/></person-group> <article-title>Pericardial delayed hyperenhancement with CMR imaging in patients with constrictive pericarditis undergoing surgical pericardiectomy: a case series with histopathological correlation</article-title>. <source>JACC Cardiovasc Imaging</source>. (<year>2011</year>) <volume>4</volume>:<fpage>1180</fpage>&#x2013;<lpage>91</lpage>. <pub-id pub-id-type="doi">10.1016/j.jcmg.2011.08.011</pub-id><pub-id pub-id-type="pmid">22093269</pub-id></citation></ref>
<ref id="B34"><label>34.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Won Hyeon</surname><given-names>C</given-names></name><name><surname>Kyung Yi</surname><given-names>H</given-names></name><name><surname>Kyoung Kim</surname><given-names>E</given-names></name><name><surname>Park</surname><given-names>S-J</given-names></name><name><surname>Lee</surname><given-names>S-C</given-names></name><name><surname>Woo Park</surname><given-names>S</given-names></name><etal/></person-group> <article-title>The role of 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography in the differential diagnosis of pericardial disease</article-title>. <source>Sci Rep</source>. (<year>2020</year>) <volume>10</volume>:<fpage>21524</fpage>. <pub-id pub-id-type="doi">10.1038/s41598-020-78581-y</pub-id><pub-id pub-id-type="pmid">33299053</pub-id></citation></ref>
<ref id="B35"><label>35.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ntsekhe</surname><given-names>M</given-names></name><name><surname>Matthews</surname><given-names>K</given-names></name><name><surname>Wolske</surname><given-names>J</given-names></name><name><surname>Badri</surname><given-names>M</given-names></name><name><surname>Wilkinson</surname><given-names>KA</given-names></name><name><surname>Wilkinson</surname><given-names>RJ</given-names></name><etal/></person-group> <article-title>Scientific letter: Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) and Galectin-3 levels in tuberculous pericardial effusion: implications for pathogenesis and prevention of pericardial constriction</article-title>. <source>Heart</source>. (<year>2012</year>) <volume>98</volume>:<fpage>1326</fpage>&#x2013;<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1136/heartjnl-2012-302196</pub-id><pub-id pub-id-type="pmid">22842991</pub-id></citation></ref>
<ref id="B36"><label>36.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ntsekhe</surname><given-names>M</given-names></name><name><surname>Matthews</surname><given-names>K</given-names></name><name><surname>Syed</surname><given-names>FF</given-names></name><name><surname>Deffur</surname><given-names>A</given-names></name><name><surname>Badri</surname><given-names>M</given-names></name><name><surname>Commerford</surname><given-names>PJ</given-names></name><etal/></person-group> <article-title>Prevalence, hemodynamics, and cytokine profile of effusive-constrictive pericarditis in patients with tuberculous pericardial effusion</article-title>. <source>PLoS One</source>. (<year>2013</year>) <volume>8</volume>:<fpage>10</fpage>. <pub-id pub-id-type="doi">10.1371/journal.pone.0077532</pub-id></citation></ref>
<ref id="B37"><label>37.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wynn</surname><given-names>TA</given-names></name></person-group>. <article-title>Cellular and molecular mechanisms of fibrosis</article-title>. <source>J Pathol</source>. (<year>2008</year>) <volume>214</volume>:<fpage>199</fpage>&#x2013;<lpage>210</lpage>. <pub-id pub-id-type="doi">10.1002/path.2277</pub-id><pub-id pub-id-type="pmid">18161745</pub-id></citation></ref>
<ref id="B38"><label>38.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kasem-Suwan</surname><given-names>P</given-names></name><name><surname>Potjalongsilp</surname><given-names>S</given-names></name></person-group>. <article-title>Predictors of constrictive pericarditis after tuberculous pericarditis</article-title>. <source>Heart</source>. (<year>1995</year>) <volume>73</volume>:<fpage>187</fpage>&#x2013;<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1136/hrt.73.2.187</pub-id></citation></ref>
<ref id="B39"><label>39.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kumar</surname><given-names>A</given-names></name><name><surname>Sato</surname><given-names>K</given-names></name><name><surname>Yzeiraj</surname><given-names>E</given-names></name><name><surname>Betancor</surname><given-names>J</given-names></name><name><surname>Lin</surname><given-names>L</given-names></name><name><surname>Tamarappoo</surname><given-names>BK</given-names></name><etal/></person-group> <article-title>Quantitative pericardial delayed hyperenhancement informs clinical course in recurrent pericarditis</article-title>. <source>JACC Cardiovasc Imaging</source>. (<year>2017</year>) <volume>10</volume>:<fpage>1337</fpage>&#x2013;<lpage>46</lpage>. <pub-id pub-id-type="doi">10.1016/j.jcmg.2016.10.020</pub-id><pub-id pub-id-type="pmid">28330665</pub-id></citation></ref>
<ref id="B40"><label>40.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gerardin</surname><given-names>C</given-names></name><name><surname>Mageau</surname><given-names>A</given-names></name><name><surname>Benali</surname><given-names>K</given-names></name><name><surname>Jouan</surname><given-names>F</given-names></name><name><surname>Ducrocq</surname><given-names>G</given-names></name><name><surname>Alexandra</surname><given-names>JF</given-names></name><etal/></person-group> <article-title>Increased FDG-PET/CT pericardial uptake identifies acute pericarditis patients at high risk for relapse</article-title>. <source>Int J Cardiol</source>. (<year>2018</year>) <volume>271</volume>:<fpage>192</fpage>&#x2013;<lpage>4</lpage>. <pub-id pub-id-type="doi">10.1016/j.ijcard.2018.05.126</pub-id><pub-id pub-id-type="pmid">29884293</pub-id></citation></ref>
<ref id="B41"><label>41.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Imazio</surname><given-names>M</given-names></name><name><surname>Brucato</surname><given-names>A</given-names></name><name><surname>Maestroni</surname><given-names>S</given-names></name><name><surname>Cumetti</surname><given-names>D</given-names></name><name><surname>Belli</surname><given-names>R</given-names></name><name><surname>Trinchero</surname><given-names>R</given-names></name><etal/></person-group> <article-title>Risk of constrictive pericarditis after acute pericarditis</article-title>. <source>Circulation</source>. (<year>2011</year>) <volume>124</volume>:<fpage>1270</fpage>&#x2013;<lpage>5</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCULATIONAHA.111.018580</pub-id><pub-id pub-id-type="pmid">21844077</pub-id></citation></ref>
<ref id="B42"><label>42.</label><citation citation-type="journal"><person-group person-group-type="author"><name><surname>Xu</surname><given-names>B</given-names></name><name><surname>Huang</surname><given-names>SSL</given-names></name><name><surname>Jellis</surname><given-names>C</given-names></name><name><surname>Flamm</surname><given-names>SD</given-names></name></person-group>. <article-title>Diagnosis of active pericarditis by positron emission tomography (PET)/cardiac magnetic resonance (CMR) imaging</article-title>. <source>Eur Heart J</source>. (<year>2018</year>) <volume>39</volume>:<fpage>179</fpage>. <pub-id pub-id-type="doi">10.1093/eurheartj/ehv127</pub-id><pub-id pub-id-type="pmid">29096007</pub-id></citation></ref></ref-list>
</back>
</article>