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Expert Review of Cardiovascular Therapy
ISSN: 1477-9072 (Print) 1744-8344 (Online) Journal homepage: http://www.tandfonline.com/loi/ierk20
Deciphering cardiac involvement in systemic
inflammatory diseases: noninvasive tissue
characterisation using cardiac magnetic resonance
is key to improved patients’ care
Martin Gester, Elif Peker, Eike Nagel & Valentina O. Puntmann
To cite this article: Martin Gester, Elif Peker, Eike Nagel & Valentina O. Puntmann (2016):
Deciphering cardiac involvement in systemic inflammatory diseases: noninvasive tissue
characterisation using cardiac magnetic resonance is key to improved patients’ care, Expert
Review of Cardiovascular Therapy, DOI: 10.1080/14779072.2016.1226130
To link to this article: http://dx.doi.org/10.1080/14779072.2016.1226130
Accepted author version posted online: 19
Aug 2016.
Published online: 19 Aug 2016.
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1
Publisher: Taylor & Francis
Journal: Expert Review of Cardiovascular Therapy
DOI: 10.1080/14779072.2016.1226130
Deciphering cardiac involvement in systemic inflammatory diseases: noninvasive tissue
characterisation using cardiac magnetic resonance is key to improved patients’ care
Martin Gester1, BSc; Elif Peker1,2, MD; Eike Nagel1, MD, PhD; Valentina O.Puntmann1,3, MD,
PhD, FRCP;
Affiliations:
1Institute for Experimental and Translational Cardiovascular Imaging, DZHK Centre for
Cardiovascular Imaging, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.
2 Department of Radiology, Ankara University School of Medicine, Ankara, Turkey
3 Department of Cardiology, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
*Author for correspondence:
Dr Valentina O. Puntmann, Institute for Experimental and Translational Cardiovascular
Imaging, DZHK Centre for Cardiovascular Imaging; Goethe University Frankfurt, Frankfurt,
Germany; Tel.: +49 69/6301-5789; Fax: +49 69 / 6301-6374, Email: vppapers@icloud.com
2
Abstract
Introduction. Cardiac involvement in systemic inflammatory diseases (SID) has a major impact
on patients’ morbidity and mortality, yet the pathways to its recognition and management remain
poorly established.
Areas covered. Overall clinical management in SID patients is primarily guided by systemic
symptoms. Cardiovascular disease goes largely undetected, as it evolves through years of a
protracted and subclinical course. Despite the increased awareness and insights into the
mechanistic role of the inflammatory pathways, clinical management of cardiac involvement
continues to rely on diagnostic means, which are frequently insensitive, inaccurate, invasive and
rely on radiation exposure. Advanced tissue characterisation with cardiovascular magnetic
resonance (CMR) offers an accurate, non-invasive and radiation-free diagnostic method with
obvious advantages: owing to its versatile imaging readouts, it is able to inform on a range of
cardiovascular pathophysiology, as well as support safe serial examinations, informing on the
disease presence, progress and response to treatment.
Expert commentary. We summarise the recent advances in non-invasive imaging, and bridge the
novel insights into pathophysiology with future posibilities in diagnosis and manangement of SID
patients. We propose an interdisciplinary framework to screening of cardiac involvement in SID
using an indepth phenotyping of evolution of cardiovascular disease, to decipher the opportunities
to improve patients’ cardiac care.
Keywords
cardiac magnetic resonance, systemic inflammatory diseases, rheumatoid arthritis, systemic lupus
erythematosis, non-ischaemic cardiomyopathy, T1 mapping, T2 mapping, microvascular disease,
myocarditis, aortic stiffness
3
1. Introduction
Cardiac involvement in systemic inflammatory diseases (SIDs) has a major impact on patients’
morbidity and mortality, yet the pathways to its recognition and management remain poorly
established(1). Overall clinical management in these patients is primarily guided by systemic
symptoms due to involvement of joints, skin, lungs, kidneys or brain. Cardiovascular (CV) disease
(CVD) remains largely undetected as it evolves through years of sustained systemic inflammation.
The majority of the documented cardiac manifestations, which form the knowledge base for a high
burden of CVD in SIDs relate to the advanced disease manifestations. It is increasingly
understood that the natural course of CVD in SIDs is for the major part of its course subclinical
and mechanistically defined by the non-ischaemic inflammatory pathways (2-10). The assumption
that accelerated atherosclerosis and ischaemic heart disease (IHD) constitute the main CVD
presentations lacks validation in the more recent evidence based on advanced tissue
characterisation with cardiovascular magnetic resonance (CMR), which points towards the
predominant non-ischaemic inflammatory pathways, potentially leading to dilated
cardiomyopathy (DCM), heart failure (HF) (Figure 1) and arrhythmic presentations (1,4,8,11-13).
CMR offers a sensitive, accurate and non-invasive diagnostic means with obvious advantages and
suitability for its use in patients with SID. As a non-invasive and ionising radiation-free method
with versatile imaging readouts, it can inform on the whole spectrum of CVD(14) and supports
serial examinations, informing on the disease presence, progress and response to treatment(7,15).
It is important to understand that detecting and treating diffuse subclinical cardiovascular disease
requires a mind change in comparison to typical approaches in cardiology, which are driven by
symptoms, such as angina in IHD. Ischaemic diagnostic pathways, based on detection of regional
wall motion abnormalities by echocardiography and coronary anatomy (16), are relatively
sensitive, commonly inaccurate, and partially invasive, and are known to have low diagnostic
yield in investigation of non-ischaemic cardiomyopathies (10,17). SID patients provide a prime
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example, where such traditions and pathways fail, and where the opportunities afforded by novel
diagnostic methods such as CMR could make a world of difference.
CMR is unique among the CV imaging modalities in its ability to support direct myocardial tissue
characterisation, contrasting indirect approaches such as the analysis of regional wall motion
abnormalities or reduction of global function(14,15,18,19). Visualisation of gadolinium based
contrast agents or late gadolinium enhancement (LGE) is an established method for assessing
regional myocardial changes, such as ischaemic myocardial scar or replacement scar in cardiac
sarcoidosis(7,20). LGE provides diagnostic and prognostic information in a variety of cardiac
conditions, including SIDs (6,12,21). Inflammatory myocardial processes in most of SIDs are
however diffuse in nature, affecting myocardium in an uniform and global distribution, and as
such these will not be readily detected with LGE. Diffuse myocardial involvement, the hallmark
of the myocardial involvement in SID patients, includes widespread inflammation and diffuse
interstitial fibrosis. It can now be also detected non-invasively by means of quantitative tissue
characterisation (QTCs) with T1 and T2 mapping techniques (22). These novel techniques
importantly expand the ability to detect and decipher the complex pathophysiological pathways of
cardiac involvement in SIDs earlier in the course of disease(2). As the evidence is growing, the
improved means of CVD recognition and insight into disease stages will enable effective
pathways of clinical care for SID patients. In this review article, we summarise the recent
advances in non-invasive imaging, and bridge the novel insights into pathophysiology with future
possibilities in diagnosis and manangement of SID patients.
2. Why is cardiac involvement in SIDs such a challenge?
Systemic inflammatory diseases (SIDs) can be defined as a systemic involvement of at least two
(or more) organ systems, whereby the persistent inflammatory process underlies the organ injury
(8,17). Most of the knowledge on cardiac involvement in SIDs is based on the studies in systemic
lupus erhythematosus (SLE) and rheumatoid arthtritis (RA)(13). Nevertheless, systemic sclerosis,
5
cardiac sarcoidosis and vasculitides also feature importantly in this context. For many, the
suppositions of CV involvement continue to draw upon the autopsy findings(23).
CV involvement in SIDs is poorly understood and managed for a number of reasons. In the course
of systemic disease, patients will be managed by physicians of many specialities, including
rheumatologists, respiratory physicians and nephrologists, in line with systemic symptoms.
Cardiologists would become involved only rarely, and if, late in the course of disease. The
protracted and indolent subclinical course, overshadowed by systemic symptoms, rarely generates
a convincing cardiac presentation. Low physicial activity due to comorbidities further obscures the
insight into the state of cardiac disease. Also, patients are commonly young, health-aware, and
predominantly female, placing them into the “low-risk” group in classical CV risk models
(8,13,24). A brief look into the guidelines of various SIDs reveals that whereas cardiologists as a
clinical speciality are conscious about the importance of CVD in SIDs, they continue to rely on
diagnostic methods that are known to have poor sensitivity to detect intrinsic myocardial
involvement, such as transthoracic or transoesophageal echocardiography, or disregard the young
age of the SID population and the need for serial assessments, where radiation exposure should be
minimized or best avoided (16,25). Similarly to the issues with disease recognition, there is an
apparent conflict in preventive strategies. Management of traditional CV risk factors is highly
recommended in SID patients, despite the knowledge that these do not fully explain the observed
high CVD burden or the absence of randomised studies supporting the benefit (26).
A modern approach to cardiac involvement in SIDs requires to be become based on an insight
(and experience) that pathophysiology of CVD in SIDs is underscored by inflammatory pathways
and a non-ischaemic intrinsic vascular and myocardial injury, with its major impact within the
first decade of systemic disease (2,13,27-31). In RA and SLE, several mechanisms have been
proposed to the ways, in which a sustained systemic inflammatory state can lead to development
of CVD. Early studies postulated the role of accelerated and more aggressive vascular injury,
through endothelial dysfunction, dyslipidaemia and activation of coagulation cascade, leading to
premature atherosclerosis and its complications (13,32-35). More recently, however the
6
contribution of direct inflammatory myocardial involvement has also come to light. Studies in
experimental models of autoimmune myocarditis revealed a central role of autoimmunity against
own myocardial proteins as the primary (intrinsic) driver of myocardial inflammation and injury
(36,37). The exposure of myoglobin triggering the antigen-presentation reactions, is thought to be
the myocardial injury due to immune-complex deposition in the myocardial microcirculation and
perivascular tissues (as well as a direct complement-mediated cytotoxic injury particularly in SLE)
(38-41). The consequent myocardial inflammation and injury is then mediated and perpetuated via
autoimmune responses by formation of autoantibodies directed against endogenous myocardial
structural, sarcoplasmic, or sarcolemmal proteins (36,37,42). Histologically, myocardial
inflammation is characterized by interstitial oedema, fibrinoid degeneration of collagen fibres and
focal aggregates of plasma cells, monocytes, lymphocytes, and some neutrophils in the myocardial
interstitium (39). Like in infectious (viral) myocarditis, myocardial lesions with necrosis heal with
replacement fibrosis or scar, whereas chronic inflammation elsewhere promotes a build up of
interstitial fibrosis, DCM and heart failure (HF) (11,43-47). The role of inflammatory
cardiomyopathy and progression to DCM as the primary form of cardiac involvement in SIDs is
similarly increasingly recognised (1,9). The wide spectrum of presentation and clinical course of
myocardial inflammation is in part determined by the individual predisposition to develop and
steer the autoimmune response: inability to downregulate the acute autoimmune response in an
important minority of susceptible patients (with autoimmune predisposition) may promote
progression to chronic inflammatory cardiomyopathy, LV remodelling and HF (37,48,49).
Thus, the optimal concept to disease recognition and clinical management in SIDs mandates an
paradigm shift in the mainstream approaches from the narrow focus on atherosclerosis and its
ischaemic complications towards the understanding that in SIDs, the major bulk of
pathophysiology is driven by non-ischaemic intrinsic inflammatory pathways. As such, its
recognition requires integration of highly sensitive diagnostic approaches, such as by using CMR,
which will also allow comprehensive and accurate information and safe serial assessments of
disease progression and judge the response to treatment. In this we provide the background to the
7
typical CMR imaging readouts in various SIDs to illustrate the patterns and meaning of
phenotypical presentations. We strive to inform the imaging and medical community managing
SID pateints with guidance towards accurate and reliable disease recognition.
3. The many faces of cardiovascular involvement in SIDs
The many faces of clinical manifestations of CVD in SIDs are underscored by the presence of
systemic inflammation as the common mechanistic and pathophysiological denominator(33). In
SIDs, the non-ischaemic inflammatory pathways dominate throughout the most of the ‘formative’
time of CV injury. As complex and dynamic in nature, tissue characterisation by CMR offers an
unprecedented opportunity to support its detection and monitoring by in-vivo phenotyping
noninvasively and accurately (15). Compared to other imaging techniques, there are several
important advantages to CMR, most notably its non-invasiveness, radiation-free imaging, tissue
characterisation and versatile imaging readouts, allowing accurate and in-depth insights into the
complex pathophysiology of cardiac involvement in SIDs (15). Classical imaging protocols aim to
support assessment of:
1. cardiac volumes and function by cine imaging
2. diffuse myocardial disease (inflammation and fibrosis) by T1 and T2 mapping.
3. myocardial ischaemia/microvascular disease by myocardial stress-perfusion imaging
4. regional scar/fibrosis by LGE
Because of their ease and robustness, the above protocols have become routine investigations in
patients with suspected IHD, HF and cardiomyopathies(14,50). These can be performed within 20
- 45 minutes in most clinical imaging departments, delivering diagnostic images in nearly all
patients, save the small number with contraindications (such as certain medical devices) or due to
a large body size. CMR can support in-depth tissue characterisation by visualisation of regional
myocardial injury by LGE (which is commonly irreversible) and quantifiable approaches to
diffuse myocardial involvement (which is potentially modifiable). Assessment of cardiac volumes
and global systolic function in SIDs is routinely done, however less informative in early stages of
8
disease (2,3,51). On the contrary, assessment of myocardial perfusion by CMR may help to
distinguish relevant regional myocardial ischaemia due to the significant epicardial CAD(52,53)
from the more commonly encountered microvascular (endothelial) coronary disease in patients
with SID (30,54). The recommendations for conduct and technical details of the CMR protocols,
including the related evidence on diagnostic accuracy and prognostic relevance have been
published elsewhere (14,50,55).
4. Cardiac function and structure
In subclinical stages of disease most patients with SID will have normal cardiac volumes and
biventricular function (2,3,56,57). Reduction of longitudinal myocardial strain may be the earliest
sign of left ventricular (LV) functional impairment; because it relies on subendocardial myocardial
layers, it is sensitive for the presence of subendocardial ischaemia (including microvascular
disease) or ischaemic scar, but not for inflammatory myocardial involvement, which tend to affect
the outer epicardial layers first (58,59). For the same reason (i.e. longitudinal function being
relatively preserved), reduction of global systolic function will be in most patients only mild-
moderate. Severe global impairment may be found in patients that had either sustained an
ischaemic event or present in advanced stages of DCM. Furthermore, a relative increase in LV
wall thickness due to myocardial inflammation precludes detecting a small increase in LV
volumes, only to become apparent in the later stages of disease when inflammation has subsided,
walls have thinned with myocardial interstitial fibrosis. Increase in LV mass in early inflammatory
stages may be followed by either reduced LV mass due to physical inactivity, or increased LV
mass due DCM and HF (11,21,57,60,61). A further important consequence of many SIDs is the
right ventricular (RV) impairment due to pulmonary hypertension in the context of concomitant
lung disease or left-sided heart failure (1,32) (Figure 2). In pulmonary hypertension, assessment
of RV volumes by CMR is the most accurate diagnostic and prognostic method (62,63). The
relatively long period of preserved cardiac function and structure explains some of the overall
difficulty in separating the normal findings from the abnormal, solely on the basis of cardiac
structure and function, such as with echocardiography (1,64). Gross abnormalities, which
9
eventually occur once disease has progressed into advanced stages, add little beyond the
confirmation of involvement with a poor scope for reversibility.
5. Ischaemic heart disease – macro and microvascular disease
The role of atherosclerosis in contributing to considerable CV morbidity and mortality has been
particularly highlighted in patients with RA and SLE. Patients with RA and SLE have
approximately 2-7-fold higher risk of myocardial infarction, sudden death and congestive HF
compared to patients without RA/SLE, irrespective of age and or the presence of CV risk factors
(13,65-67). The insights of these early studies led to postulate the markedly higher prevalence of
atherosclerotic complications due to accentuated effects of traditional CV risk factors in the
presence of systemic inflammation(35). Whereas some studies found that the risk increases with
age and disease duration (13), others revealed that the greatest share of CV events occurs within
the first decade since the diagnosis (31). Many of these early studies lack the correlates in the
more recent literature, indicating a much smaller share of classical atherosclerotic complications,
such as myocardial infarction, strokes and peripheral vascular disease, than thought
previously(2,29,30,68,69). The two possible explanations for this discrepancy include an overall
reduced CV risk in SID patients and an improved accuracy of diagnosing CV events. Firstly,
several studies pointed out that CV risk in SID patients had been reduced over the past 2 decades.
It appears to have been mitigated by the primarily modern anti-inflammatory, and to a lesser
extent, the statin therapy (70-72). The second argument relates to the improved diagnostic means
and rigorous definitions of the actual ischaemic events, afforded by the troponin tests and the
establishment of the acute coronary syndrome (ACS) management pathways (16,73-75).
Angiographic findings of unobstructed coronary arteries in patients presenting with the ACS-like
symptoms is not uncommon; together with CMR, it enlightened the role of intrinsic inflammatory
myocardial disease, ie myocarditis in such patients (2,16,30,39,40,76,77). In SID patients, save a
single study (78), a body of evidence supports intrinsic inflammatory myocardial involvement,
DCM, or microvascular disease (2,30,68,76,79,80). Direct contribution of systemic inflammation
to the endothelial dysfunction is a proposed pathophysiological mechanism of the commonly
10
encountered microvascular coronary disease in patients with RA (28,81) (Figure 3). Similarly,
increased aortic stiffness in SID patients is better explained by microvascular disease of vasa
vasorum. Increased aortic stiffness contributes to the increased LV afterload, ventricular stiffness
and impaired systolic and diastolic function (33,60,82,83). These changes appear earlier and are
more severe in patients with SIDs compared to the general population (84). However, they appear
to be at least partially reversible by anti-inflammatory agents (82,85-87). With respect to these
revelations, early CV intervention by targeting inflammation is emerging as the crucial preventive
strategy in managing cardiac involvement in patients with SIDs.
Diagnostication of relevant regional myocardial ischaemia by CMR with adenosine-perfusion
stress-testing has several advantages in patients with SID: firstly, it has a higher diagnostic and
prognostic accuracy for detection of significant obstructive CAD in comparison to other ways of
ischaemia-testing (Figure 4A), (88-92). Secondly, evidence of regional hypoperfusion (of more
than 6/32 myocardial segments) indicates significant obstructive coronary artery disease, which
would prognostically benefit from guide coronary intervention (88,93) (94) (95). Thirdly,
adenosine-stress CMR is also highly sensitive for diagnosis ischaemia in women(96), unlike other
methods sufferring with sex-differences in diagnostic accuracy (97) (98). As such, together with
its non-invasiveness and freedom from ionizing radiation, it is a highly appropriate investigation
for the presence of ischaemia in SID patients with high prevalence of young female patients (99).
Lastly, CMR can support direct recognition of microvascular disease non-invasively. Patients will
thus benefit from achieveing the definitive diagnosis and reassurance by explanation for their
symptoms and by avoiding the numerous unnecessary future investigations procedures, which
commonly include high radiation exposure, nephrotoxic contrast agents, and procedural
complications (29,30,100-102). Also, they may benefit from anti-anginal treatment (103,104).
6. Tissue characterisation – LGE and T1/T2 mapping
The abundance of evidence behind the tissue characterisation by LGE by informing on the
underlying diagnosis, prognosis and the type of myocardial pathophysiology (ischaemic vs. non-
ischaemic, regional vs. diffuse) (15,77,105,106), has also contributed important insights into the
11
pathophysiology of cardiac involvement in SID(6,55,79,107). The presence of LGE allows
differentiation between ischaemic and non-ischaemic cardiomyopathy based on the types of LGE
patterns (ischaemic LGE: subendocardial-transmural scar within the perfusion territory of an
epicardial coronary artery, vs. non-ischaemic LGE type epicardial-transmural, not following the
regional distribution (108)), which is is important as it allows pursuing differential therapeutic
pathways (109). Furthermore, the transmurality of ischaemic myocardial scar matters in terms of
recovery of functional impairment of the affected segment with revascularisation: when less than
50% transmural, there is a high likelihood it may benefit from revascularisation (110). Non-
ischaemic type of LGE may be found between 20-50% of patients with SID and the pattern may
point towards the underlying diagnosis of SID (21). The prevalence of non-iscahemic LGE
increases with age, duration of systemic disease and advanced stage of cardiac involvement
(1,2,6,20,21,68,111). In DCM, a common consequence of cardiac involvement in SIDs, it relates
to worse survival and greater incidence of HF (11,61). The direct prognostic evidence on LGE in
most of the SIDs is lacking, save for cardiac sarcoidosis, where the commonly extensive LGE
relates to the arrhythmic burden and sudden death, and as such adopted into the Heart Rhythm
Society diagnostic critera for cardiac involvement in sarcoidosis, as well as in guiding device
therapy (12,112).
Recent knowledge from experimental models of viral and autoimmune myocarditis elucidated the
role of inflammatory cardiomyopathy and progression to DCM as the primary form of cardiac
involvement in SIDs (1,9,36). The wide spectrum of presentation and clinical course of
myocarditis is in part determined by the individual predisposition: inability to downregulate the
acute autoimmune response in susceptible patients (in particulary those with autoimmune
predisposition) will lead to chronic inflammatory cardiomyopathy, DCM and HF (37,48,49).
These insights resonate with the findings of QTCs imaging based on T1 and T2 mapping (22).
These show that diffuse myocardial inflammation is well underway already in subclinical stages
including in patients with SLE, RA, systemic sclerosis and cardiac sarcoidosis
(2,3,5,7,111)(Figure 4). Studies have also shown a good correlation between QTCs and
12
histological evidence of myocardial inflammation (113,114). These novel measures are markedly
more sensitive in detecting myocardial inflammation compared to the old ways by Lake Louise
Criteria based on visualisation of enhanced areas on T2 weighted imaging and on regional
myocardial disease by LGE(9). Both visualisation approaches (i.e. T2 imaging and LGE) are
ineffective in detection of diffuse myocardial processes, which underscores the cardiomyopathic
involvement in SID patients, including widespread myocardial inflammation and diffuse
interstitial fibrosis. To this end, T1 and T2 mapping are complementary in informing on
cardiomyopathic processes in SID; native T1 is able to discriminate abnormal myocardium (due to
different cardiomyopathic substrates, including myocardial inflammation, infiltrayion of diffuse
fibrosis) with high diagnostic and prognostic accuracy ((2,11,43,115,116)). On the contrary, native
T2 mapping is more specific for myocardial oedema/inflammation ((114,117,118), however, it is
less sensitive to other substrates underlying an abnormal myocardium (114). Therefore, a
combination of both measures is of a critical importance in patients with SID: native T1 identifies
subjects at risk of (or with) cardiomyopathy, whereas native T2 informs on activity of
inflammatory involvement. Although the QTCs based evidence seems to point into similar
direction, a considerable technical diversification of T1 and T2 mapping approaches between
various users and vendors remains a shortcoming of these highly promising methods, necessitating
the users to undertake on-site standardisation of methods, including derivation of normal values
(22). Yet, the development of an accurate and non-invasive diagnostic method for identification of
myocardial inflammation is central to the evolution of effective clinical management of
inflammatory cardiomyopathies, including in SIDs. The current diagnostic standard relies on
histological evidence of myocardial inflammation by endomyocardial biopsy (EMB). This
complex and invasive procedure involves procedural risks as well as radiation; it has variable
diagnostic yield, and with expertise largely limited to the tertiary centres, this is variably utilised
in clinical practice. The standard Dallas pathological criteria for the definition of myocarditis
require an inflammatory cellular infiltrate and associated with myocyte necrosis, which differs
from characteristic ischemic heart damage (119). Allthough these criteria are highly specific for
13
differentiation of myocardial inflammation from ischaemic myocardial injury, they have a
relatively low sensitivity for an overall detection of myocarditis, as they depend on a number
biopsy samples and a type of technique employed, explaining high inter-observer variability in
data analysis (119,120). The lack of precision of the Dallas criteria has been traditionally
explained by the sampling error due to a ‘patchy’ involvement of the myocardium (121); this
postulation contrasts the modern evidence of diffuse inflammatory involvement (2,3,122,123) and
is likely to be explained by the predominance of EMB- evidence in late presentations with chronic
or healed myocarditis in DCM and HF (114,121). Also, histological assessment misses a vital
inflammatory tissue component – myocardial oedema (9,120), which is the primary driver of the
signal detected by QTCs(117,122). Whereas histological insights can undoubtfully be informative,
the need for serial assessments to monitor progress and treatment as well as the absence of
consequent management pathways further deters the use of EMB in clinical routine. Here, non-
invasive, radiation-free and comprehensive CMR approach provides the optimal approach to
diagnosis of myocardial inflammation without the procedural risks including cardiac perforation,
iatrogenic mitral regurgitation or stroke (124). As clarified above, functional abnormalities in
myocarditis are commonly subtle and, if present, they affect myocardium globally, hence,
myocarditis cannot be diagnosed by echocardiography, rendering the assumption of a normal
echocardiogram highly inaccurate in myocarditis(1,57). Small pericardial effusion is a common,
yet very non-specific finding. More specific is the demonstration of pericarditis by evidence of
thickened pericardial layers and pericardial enhancement (Figure 5). Thickened and enhanced
pericardium may resolve with anti-inflammatory treatment (125,126).
14
7. Expert commentary
Cardiac involvement in systemic inflammatory diseases (SIDs) has a major impact on patients’
morbidity and mortality, yet the pathways to its recognition and management remain poorly
established (1). Overall clinical management in these patients is primarily guided by systemic
symptoms due to involvement of joints, skin, lungs, kidneys or brain. Cardiovascular disease
remains largely undetected as it evolves through years of low-grade systemic inflammation
(Figure 6): the majority of the documented cardiac manifestations, which form the knowledge
base for a high burden of CVD in SIDs relate to the advanced disease manifestations, including
heart failure (HF) and arrhythmic presentations. Despite the increased awareness of CVD burden
in SID patients and improved insight into the natural course of heart disease with emphasis on the
mechanistic role of the inflammatory pathways, approaches to diagnosis and management rely on
relatively insensitive, inaccurate and commonly invasive diagnostic means. The once thought to
be the predominant share of CVD, ischaemic heart disease, was not reproduced in the more recent
evidence based on CMR, which rather suggests the high prevalence of primary inflammatory
myocardial involvement.
Systematic research by in-depth non-invasive pathophysiological phenotyping, such as with
soluble biomarkers and CMR, is needed, to clarify the type and the evolution of cardiovascular
dysfunction in SIDs. This should ideally starting early in the course of systemic disease, such as at
the time of first diagnosis (Figure 7). Such evidence would inform on the opportunities to
streamline and improve the SID patients’ cardiac care. As non-invasive highly sensitive diagnostic
method with versatile and accurate imaging readouts informing on a range of cardiac disease, it is
well suited to decipher the complex cardiac involvement in SIDs, as well as support longitudinal
assessments. Advent of quantitative tissue characterisation by T1 and T2 mapping techniques
particularly help to expand the ability to detect inflammatory myocardial involvement; as it is
partially reversible, QTCs may provide the essential first step to effective disease recognition and
clinical management.
15
8. Five-year view
QTCs are key to deciphering myocardial inflammation: T1 and T2 mapping values are able to
detect diffuse myocardial disease and myocardial oedema in particular (2,114,117,122,127).
Native T1 provides an accurate and reliable recognition of abnormal myocardium, either due to
diffuse myocardial fibrosis, inflammation, infiltration or hypertrophy (43,116,122). Addition of
T2 mapping helps to specifically elucidate on the presence of myocardial oedema(117,118). Both
reflect the intracellular and diffuse interstitial component of inflammation within a single
parameter. Native T1 and T2 can be used to determine the stages of myocarditis; native values will
be very high in acute (and active) myocarditis, whereas as the inflammatory response (i.e. oedema
and hyperaemia) regresses after the early acute stage, either with spontaneous resolution or
treatment (7,122), native T1 and T2 show progressive reduction over the time. Whereas native T2
values can fully normalize with resolution of inflammation, persistently abnormal native T1
values indicate transition into pathophysiological remodelling with accumulation of diffuse
fibrosis and DCM. In DCM, native T1 relates to their functional impairment, as well as informs on
their significantly worse prognosis, over and above LGE and ejection fraction (11,60,116). Thus,
CMR together with QTCs provide a most promising novel approach in deciphering the presence
and stages of inflammatory cardiomyopathy, potentially identifying the opportunities for targeted
treatment in the acute stage of disease.
16
9. Key issues
• Cardiovascular involvement in SIDs has a major prognostic impact, yet pathways to its
recognition and management remain rudimentary.
• The many faces of clinical manifestations of CVD in SIDs are underscored by the presence
of systemic inflammation as the common mechanistic and pathophysiological
denominaton.
• In SIDs, the non-ischaemic inflammatory pathways dominate throughout the protracted
and indolent subclinical ‘formative’ time of cardiovascular injury course, which is
overshadowed by systemic symptoms.
• As complex and dynamic in nature, tissue characterisation by CMR offers an
unprecedented opportunity to support its detection and monitoring by in-vivo phenotyping
noninvasively, allowing to detect changes in a subclinical phase of the disease and to guide
treatment of SID patients.
• There is a need for future systematic research, which should include linking imaging,
pathophysiology and biomarkers, to support development of interdisciplinary screening
programme to support timely delivery of cardiac care in patients with SID.
Funding
This paper was not funded.
Declaration of interest
V Puntmann and E Nagel hold a patent of invention for a method for differentiation of normal
myocardium from diffuse disease using T1-mapping in nonischaemic cardiomyopathies and others
(based on PR-MS 33.297, PR-MS 33.837, PR-MS 33.654) (with no financial interest). The
Institute of Experimental and Translational Cardiovascular Imaging is supported by the German
Ministry of Education and Research via the German Centre for Cardiovascular Research (DZHK)
17
to V Puntmann and E Nagel. E Peker is supported by the Turkish Ministry of Health and Science.
The authors have no other relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject matter or materials discussed
in the manuscript apart from those disclosed.
References
Reference annotations
* Of interest
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26
Figure 1. Dilated cardiomyopathy in SLE. CMR findings in a young SLE patient (<20 of age;
SLE diagnosis at age o 12) with no previous cardiac cardiac symptoms, undergoing screening for
cardiac involvement. CMR revealed dilated left ventricle (indexed EDV: 152 ml/m2 (normal
range: 98-62ml/m2) with severely impaired global systolic function (ejection fraction: 20%) with
no evidence of LGE(77). Biatrial dilatation suggests a protracted chronic course. In this patient,
native T1 was raised > 4SD deviations, placing the patient in the high risk group for poor outcome
((11). Native T2 (42 msec) was within normal range (41-49msec)(118), indicating absence of
active myocardial inflammation. In summary, these findings are consistent with non-ischaemic
dilative cardiomyopathy.
Figure 1
SAX ED SAX ES
4CH3CH
Cines LGE
SAX
4CH
27
Figure 2. CMR findings in pulmonary hypertension in the context of SID. A 40~year old
patient with a known diagnosis of systemic sclerosis, presenting for screening of cardiac
involvement. CMR revealed non-dilated right ventricle (indexed EDV 108 ml/m2 (normal range:
42-118) with mildly impaired global RV systolic function (RV-EF: 37%). LV volumes were
reduced. There is a marked D-shaped ventricle with systolic flattening of interventricular septum
(paradoxic septal shift in end-diastole – yellow arrow). LGE imaging reveals patches of
replacement fibrosis in RV insertion points (orange arrows) (128),(129). Septal native T1 was
elevated at 1152 msec (3.0T: normal range <1090 msec)(130).
Figure 2
SAX -ED SAX -ES
4CH -ES
4CH -ED
LGE - MID
LGE - AP
28
Figure 3. Representative images of typical CMR readouts in regional myocardial ischaemia
(A) vs. microvascualar disease (B): (A) regional myocardial ischaemia (A) due to obstructive
coronary artery disease, yielding a perfusion defect in the right coronary artery territory (RCA:
yellow arrows). (B): diffuse (sub)endothelial microvascular disease of vasa vasorum
(hypoperfusion - yellow arrows), but preserved epicardial blood entry (orange arrows) due to
cytokine-induced endothelial dysfunction in patients with SLE(81). Modified from Varma et al.
(30) with permission from Elsevier.
Figure 3.
29
Figure 4. CMR findings in acute lupus myocarditis. Native T1 is strongly elevated. Note an
increased T2 signal (yellow arrows) and diffuse patchy intramyocardial LGE (red arrows)
corresponding to the inflammatory overspill of myocardial oedema and regional scarring.
Figure 4
3T
Normal range:
<1090msec (1050 ± 20 ms)
1315 ms
T1 map
1297 ms
SAX
LGE
T2-STIR
4CH3CH
Native T1
30
Figure 5. CMR findings in SLE related chronic pericarditis presenting with atypical chest
pain. LGE imaging reveals circumferrential pericardial enhancement in a patient wih SLE (yellow
arrows). There are no signs of constrictive pathophysiology, such as paradoxal septal shift on cine
imaging Native T1 was normal (1078 msec (3.0T: normal range <1090 msec)(130). Findings are
consistent with isolated pericarditis without evidence of myocardial involvement.
Figure 5.
SAX-ED
SAX-ES
4CH-ED
4CH-ES
LGE
Cines
SAX-ED
4CH-ED
31
Figure 6. Schematic representation of the likely development of cardiovascular disease in SID
patients and proposed role for CMR for identification of cardiac complications and guide therapy.
Time
diagnosis of
SID
ongoing disease and remodelling
elevated biomarkers
therapy
cardiac mortality
symptoms
SID subclinical
CMR
serial check-up
re-evaluation
Awareness in
primary care
Interdisciplinary
approach
Personalised therapy and
monitoring
Guiding way to
specialists Eviden ce Better care
Figure 6.
32
Figure 7. Proposed concept for development of a comprehensive interdisciplinary screening
programme to support timely cardiac care in patients with SID. In view of a protracted subclinical
course, non-specific symptoms and diverse phenotype of cardiac involvement in SID patients,
screening with CMR is crucial to allow characterisation of the different pathophysiological
pathways and allow early insitituon of correct therapy. Screening would begin at the time of the
diagnosis of SID. As these patients are young, commonly women of childbearing years, they will
require repetitive cardiac investigations, hence nonivasive and radiation-free methods are
preferable.
Practice Guidelines update?
CMR ScreeningBiomarker Screening
enrol patients in screening programs & multicenter-RCT
Follow-up (biomarkers, CMR, outcome)
reevaluate risk factors, monitoring and therapy
Towards individualized cardiac care in SID patients
Imaging
CardiologyRheumatology
primary care
Im
CRh
PC
Im
C
Rh
PC
Im
CRh
CRh
Im
CRh
PC
CRh
PC
First diagnosis of SID
Figure 7.
33
Table 1. CMR imaging protocol in patients with SIDs follow the basic SCMR recommendations.
Imaging readouts Physiology examined Measure/marker Pathological findings
Cine Imaging Cardiac volumes LV-EDV, LV-EVS, LV-SV Dilated LV
RV-EDV, RV-EVS, RV-SV Dilated RV
Global systolic function LV-EF Reduced EF
RV-EF
Regional systolic function RWMA Akinesia, hypokinesia,
septal shifts
Cardiac plasticity LV wall thickness (LVWT) and mass Increased LVWT
Increased LV mass
Myocardial deformation Global longitudinal strain (GLS) Reduced GLS
T1 mapping Presence of myocardial
disease
Native T1, ECV Interstitial fibrosis
Myocardial inflammation
Myocardial infiltration
T2 mapping Presence of myocardial
inflammation
Native T2 Myocardial inflammation
LGE Presence of regionally
expanded extracellular
space
Visualisation of LGE Replacement fibrosis:
postinfarction scar; non-
ischaemic patchy fibrosis
Regional necrosis
Pericardial enhancement
Adenosine-stress perfusion Significant obstructive
coronary artery disease
Regional hypoperfusion Ischaemic heart disease
Endothelial function of
coronary vasa vasorum
Subendocardial circumferential
hypoperfusion
Microvascular disease
