Towards the Clinical Management of Cardiac Involvement in Systemic Inflammatory Conditions—a Central Role for CMR

Abstract

Purpose of Review
Anti-inflammatory therapies in systemic inflammatory diseases (SID) improve disease-associated disability and may also reduce cardiovascular events. Further optimization of treatment to directly target the inflammation affecting the cardiovascular system represents a potential goal of contemporary treatment. Yet, lack of non-invasive means to detect cardiovascular involvement and to monitor the response to treatment limit such advancements. This is also reflected in the recent 2017 ESC position paper on clinical management of cardiac involvement in SIDs, whose recommendations continue to rely on insensitive, radiation-heavy and invasive diagnostic methods. Absence of evidence and the context of a life-long chronic disease, necessitating ongoing monitoring and serial assessments, puts such recommendations in question. The growing evidence-base for the performance of cardiovascular magnetic resonance (CMR) in patients with SID, and especially of T1 and T2 mapping, offers a viable pathway towards identification of cardiovascular involvement and may potentially guide cardiovascular-specific therapies.

Recent Findings
In this review, we appraise the current evidence for the role of CMR in management of cardiac involvement patients with SID.

Summary
We propose an interdisciplinary framework with a central role for CMR to support the clinical management of cardiac involvement in SID patients.

Full text

CARDIAC MAGNETIC RESONANCE (V PUNTMANN AND E NAGEL, SECTION EDITORS)
Towards the Clinical Management of Cardiac Involvement in Systemic
Inflammatory Conditions—a Central Role for CMR
Lea Winau
1
&Eike Nagel
1,2
&Eva Herrmann
3
&Valentina O. Puntmann
1,2
#Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Purpose of Review Anti-inflammatory therapies in systemic inflammatory diseases (SID) improve disease-associated disability
and may also reduce cardiovascular events. Further optimization of treatment to directly target the inflammation affecting the
cardiovascular system represents a potential goal of contemporary treatment. Yet, lack of non-invasive means to detect cardio-
vascular involvement and to monitor the response to treatment limit such advancements. This is also reflected in the recent 2017
ESC position paper on clinical management of cardiac involvement in SIDs, whose recommendations continue to rely on
insensitive, radiation-heavy and invasive diagnostic methods. Absence of evidence and the context of a life-long chronic disease,
necessitating ongoing monitoring and serial assessments, puts such recommendations in question. The growing evidence-base
for the performance of cardiovascular magnetic resonance (CMR) in patients with SID, and especially of T1 and T2 mapping,
offers a viable pathway towards identification of cardiovascular involvement and may potentially guide cardiovascular-specific
therapies.
Recent Findings In this review, we appraise the current evidence for the role of CMR in management of cardiac involvement
patients with SID.
Summary We propose an interdisciplinary framework with a central role for CMR to support the clinical management of cardiac
involvement in SID patients.
Keywords Cardiovascular magnetic resonance .Systemic inflammatory diseases .Rheumatoid arthritis .Systemic lupus
erythematosus .Cardiac sarcoidosis .Non-ischaemic cardiomyopathy .T1 mapping .T2 mapping
Introduction
Anti-inflammatory therapies in systemic inflammatory dis-
eases (SID) have led to considerable improvement of
disease-associated symptoms and disability. Incidentally,
these novel therapies also contributed favourably towards
the reduction of cardiac morbidity and mortality, an important
outcome-defining corollary in these patients [1–3]. The ob-
served reduction of cardiovascular burden is auxiliary to the
anti-inflammatory treatment of the systemic disease. To target
the cardiovascular inflammatory injury directly would be the
next meaningful step, given its major impact on the overall
outcome [4]. Several issues, however, get in a way of devel-
oping cardiac-focused management pathways. Firstly, owing
to plethora of SID entities, patients are being looked after by
several medical specialties with focused attention to the sys-
temic (non-cardiac) symptoms. Secondly, the rigid routines of
classical cardiology practice, which are modelled on classical
symptoms of atherosclerotic heart disease and employ insen-
sitive methods for detection of myocardial inflammation,
make an integration of SID patients with paucity of symptoms
or rather atypical presentations particularly difficult. Thirdly,
there is a prevailingly poor grasp about the complex, dynamic
and foremost subclinical evolution of disease. The knowledge
is based on numerous case reports, a small number of
This article is part of the Topical Collection on Cardiac Magnetic
Resonance
*Valentina O. Puntmann
vppapers@icloud.com
1
Institute for Experimental and Translational Cardiovascular Imaging,
DZHK Centre for Cardiovascular Imaging, Goethe University
Hospital Frankfurt, Frankfurt am Main, Germany
2
Department of Cardiology, Goethe University Hospital Frankfurt,
Frankfurt am Main, Germany
3
DZHK Institute of Biostatistics and Mathematical Modelling at
Goethe University Frankfurt, Frankfurt am Main, Germany
Current Cardiovascular Imaging Reports (2018) 11:11
https://doi.org/10.1007/s12410-018-9451-7

systematic studies with highly selected patient groups (autop-
sy work included), allowing scattered snapshots rather than
methodological characterisation of a heterogeneous disease.
Larger outcome studies are drawn from retrospective registries
with inadequate phenotyping; cardiac involvement is com-
monly defined by results of troponin tests, echocardiography
and cardiac catheterisation, with no direct assessment of the
inflammatory vascular and myocardial tissue processes [5].
Many of these limitations have also been acknowledged in
the recent 2017 ESC position paper for management of cardi-
ac involvement in SIDs [6•]. Finally, there is a central issue of
a lack of non-invasive means to effectively detect cardiovas-
cular involvement and monitor response to treatment. The
recommendations continue to rely insensitive, radiation-
heavy and invasive diagnostic methods, such as
endomyocardial biopsy (EMB), to support clinical manage-
ment. Clearly, the current recommendations are poorly
evidence-based and largely unsuitable for the use in young
patients. Moreover, the context of life-long chronic disease
necessitates long-term monitoring of inflammatory cardiac in-
volvement through serial assessments. Given that SID patients
receive anti-inflammatory treatment anyway for treatment of
systemic symptoms, these rather unappealing cardiac recom-
mendations will unlikely result in marked improvement of
cardiovascular aspects. The statement is scarce on the highly
relevant insights derived by cardiovascular magnetic reso-
nance (CMR), in particular, the potential offered by the tissue
mapping methods. As an accurate, non-invasive, radiation-
free method, CMR makes a perfect choice for detection and
monitoring of cardiovascular involvement in patients with
SID [7,8]. In this review, we reappraise the current evidence
on the role of CMR in management of patients with SID. We
propose an interdisciplinary framework for screening of
cardiac involvement in SID with a central role for CMR,
allowing the support of diagnosis and management of SID
patients.
Why Is CMR an Excellent Choice in Patients
with SID
The natural course of cardiac involvement in SIDs is for the
major part subclinical in young patients, who are also com-
monly overwhelmed by symptoms in other organ systems.
Cardiac symptoms, albeit atypical, rarely occur early in the
course of systemic disease [9–12]. More commonly, the first
decade following diagnosis is a period of intense systemic and
silent cardiac inflammatory involvement [5,13,14](Fig.1).
In a small proportion of patients, this would eventually culmi-
nate into manifest cardiac decompensation and death from
heart failure (with an autopsy evidence of cardiac inflamma-
tory involvement). Although the many SID entities are
characterised by pathophysiologically different auto-immune
and inflammatory mechanisms, they have somewhat similar
patterns of cardiovascular involvement. These are a result of
either direct inflammatory myocardial injury—myocarditis
[15–21,22•]—or are mediated via vasculitic coronary or aor-
tic involvement, endothelial dysfunction and microvascular
disease [8,23–26]. Evidence derived through CMR contrib-
uted a number of the unprecedented pathophysiological in-
sights, non-invasively,invivo(Table1). Firstly, it reiterated
the notion that myocardial damage is primarily caused by
myocardial inflammation (i.e. non-ischaemic in nature), by
reclassifying the ACS-like troponin-positive events without
a definite culprit lesion into protracted and indolent course
of myocarditis [15,32,33](Fig.2). Secondly, it clarified that
Manifest systemic SID
An-inflammatory therapy
SID subclinical
Awareness in
primary care Interdisciplinary approach
CMR monitoring and guiding of therapy
ongoing disease and remodelling
Cardiac morbidity and mortality in SIDs
Nave T2
Nave T1
Systemic symptoms Cardiac symptoms
CMR screening
Fig. 1 Cardiac involvement in
SID. Schematic representation of
key development stages and
overlap with systemic disease
including the proposed role for
CMR for the identification of
cardiac complications and therapy
guidance
11 Page 2 of 14 Curr Cardiovasc Imaging Rep (2018) 11:11

Table 1 Overview of studies using CMR in SID
Study SID No. of patients Native T1 SID vs.
Control
Native t2 SID vs.
Control
Field strength Main findings
Puntmann VO,
2013 [17]
SLE 33 1152 vs. 1056 ms 3 Diffuse myocardial fibrosis and ongoing inflammation shown
by T1 and T2, correlating with LGE and strain.
Zhang et al., 2014 [16] SLE 24 981 vs. 963 ms 58 vs. 52 ms 1.5 Native T2 is increased in SLE, native T1 is not different from
normal in this study.
Ntusi N, 2014 [27] SSC 191 1007 vs. 958 ms 1.5 Native T1 is increased in SSC and correlates with disease
activity and severity.
Ntusi N, 2015 [18] RA 39 973 vs. 961 msec 1.5 Increased native T1 suggests diffuse myocardial fibrosis in RA.
Barison A, 2015 [28] SSC 30 911 vs. 890msec 1.5 Native T1 is not significantly increased.
Hinojar R, 2016 [15] SLE 76 1176 vs. 1057 msec 65 vs. 45 msec 3 Native T1 and T2 are increased in SLE patients; 91% above 2SD;
71% above 5 SD in disease recognition and response to treatment.
Greulich S, 2016 [94] SARC 61 994 vs. 960 msec 52 vs. 49 msec 1,5 Native T1 and T2 display cardiac involvement in sarcoidosis.
Puntmann VO, 2017 [22] SARC 53 1139 vs. 1052 msec 54 vs.45 msec 3 T1 is a strong predictor for disease and is also increased and
treatment responsive in sarcoidosis.
Hromadka M, 2017 [95] SSC 33 1258.9 vs. 1192.2 msec 3 Asymptomatic cardiac involvement is common in SSC patients
with focal as well as diffuse myocardial fibrosis.
Wu R, 2018 [96] SLE 24 1227 vs. 1174 mesc 3 Native T1 is significantly increased in SLE.
Holmström M, 2016 [97] RA 49 1173 vs 1053 msec
1011 vs. 976msec
3
1,5
Significantly higher native T1 and T2 values describe diffuse
myocardial fibrosis and inflammation in RA patients.
Greulich S, 2017 [98] ANCA pos.
vasculitis
37 988 vs. 952 msec 53 vs. 49 msec 1,5 Native T1 and T2are increased and appear independent from
LGE in ANCA pos. vasculitis.
Microvascular disease
Study SID No. of Patients Technique Present in n(%) Main finding
Ishimori ML, 2011 [29] SLE 18 Adenosine stress
perfusion imaging
8 (44%) Microvascular disease detected by adenosine stress perfusion in SLE.
Varm a 2 01 4 [ 24] SLE 27 Adenosine stress
perfusion imaging
8(30%) Microvascular disease detected by adenosine stress perfusion in SLE.
Late Gadolinium Enhancement
Study SID No. of Patients Present in n(%) Main finding
Raman SV, 2012 [25] CSS 19 9(45%) LGE detecting cardiac involvement.
Greulich S, 2013 [21] SARC 155 40(26%) LGE as a predictor for cardiac death in SARC
Puntmann VO, 2013 [17] SLE 33 20(61%) LGE detecting subclinical cardiac involvement
Marmursztejn J, 2013 [31] CSS 20 14(70%) The presence of LGE localises subclinical active lesions, i.e.
fibrosis or ongoing inflammation.
Di Cesare E, 2013 [30] SSC 58 25(43%) LGE is a valid method to detect cardiac involvement
Ntusi N, 2014 [27] SSC 19 10(53%) LGE detecting subclinical cardiac involvement
Ntusi N, 2015 [18] RA 39 46% LGE detecting subclinical cardiac involvement
Puntmann VO, 2017 [22] SARC 54 34% LGE detecting subclinical cardiac involvement
Holmström M, 2016 [97] RA 49 55% LGE detected in combination with systolic and diastolic
impairment in RA.
Varm a 2 01 5 [ 24] SLE 27 11 (44%)
24(89%)
LGE detecting subclinical coronary vasculitis by Myocardial
LGE Diffuse coronary LGE
SLE systemic lupus erythematosus, SID systemic inflammatory disease, SSC systemic sclerosis, CCS Churg-Strauss syndrome, SARC sarcoidosis, RA rheumatoid arthritis
Curr Cardiovasc Imaging Rep (2018) 11:11 Page 3 of 14 11

a classic atherothrombotic ischaemic injury [34] is rare, as
substantiated by a prevalently absent ischaemic type of late
gadolinium enhancement (LGE) in SID patients, a gold-
standard non-invasive method to demonstrate a post-
infarction scar. Thirdly, assessment of cardiac volumes and
function using CMR is more accurate than with echocardiog-
raphy, thus allowing an early detection of cardiac enlargement
or functional deterioration. This is important, given that an
early start of anti-remodelling treatment can be rewarding
[33,35](Fig.3). Fourthly, the capabilities of CMR myocardial
perfusion imaging allow insight into the regional (spatial), but
also temporal (dynamic) information about myocardial blood
flow distribution. This capability, which is unique to CMR
[39,40], enables to reliably distinguish between classical re-
gional ischaemia due to obstructive epicardial coronary artery
disease, such as in stable angina, and diffuse circumferential
subendocardial hypoperfusion due to microvascular disease,
with endothelial dysfunction substantiating an inherent path-
ophysiological linkage between systemic and myocardial in-
flammation [41] (Fig. 4). Such distinction is an important
clinical management step in SID patients, as microvascular
dysfunction is highly prevalent, and a correct diagnosis of
microvascular dysfunction will not only offer reassurance
but also avoid the unnecessary and futile investigations, com-
monly in vain of radiation-heavy coronary catheterisations
and nuclear medicine imaging methods. Many of the above-
mentioned insights are based on the studies performed in pa-
tients with no overt cardiac symptoms and typically much
younger subjects, than routinely seen in cardiological practice
[17,18,24,27–30,43]. Collectively, this new knowledge puts
in question the traditional assumption of the accelerated ath-
erosclerotic heart disease, as the main driver of cardiac in-
volvementinSID[44,45]. This may still be relevant in an
older patient with primarily vasculitic-type of SID, such as
rheumatoid arthritis; however, even in this disease-subgroup,
the subclinical inflammatory myocardial involvement is read-
ily demonstrable early in the course of systemic disease [18,
46]. The pathophysiological importance of myocardial in-
flammation has been further reinforced by novel myocardial
tissue measures, such as T1 and T2 mapping, which directly
reflect altered tissue magnetisation [47] and have been report-
ed in a number of SID conditions (Fig. 5). The potential for
improved management of cardiac involvement in SID borne
by these measures cannot be overemphasised: measurements
are obtained non-invasively in a course of short acquisitions
and without any contrast agents. T1 and T2 mapping measure-
ments reflect disease severity and, by way of serial assess-
ments, disease activity. They track the response to anti-
inflammatory treatment, thus informing on the scope for re-
versibility and recovery of cardiac involvement [15,22•]
(Fig. 6). Finally, T1 mapping also strongly relates to progno-
sis; its predictive associations with outcome in non-ischaemic
cardiomyopathy strongly outperform the traditional risk mea-
sures, such as LV ejection fraction (LVEF) or the presence of
LGE [36] (Fig. 7). Taken together, these advances offer a
scope for tremendous progress and a true non-invasive man-
agement pathway, allowing a paradigm shift of clinical man-
agement from the non-sensitive, invasive and radiation-heavy
methods towards patient-friendly and safe assessments (non-
invasive, radiation-free and contrast-free), which can
Lupus
myocardis
Sarcoid
myocardis
Nave T1 1095 msec (1.5T <1000 msec )
Nave T1 1114 msec (1.5T <1000 msec )
Fig. 2 CMR findings in acute SID myocarditis. Upper panel: Acute myocarditis, lower panel: acute sarcoid myocarditis. Native 1 is strongly elevated.
Note diffuse patchy intramyocardial LGE (red/yellow arrows) corresponding to the inflammatory overspill of myocardial oedema and regional scarring
11 Page 4 of 14 Curr Cardiovasc Imaging Rep (2018) 11:11

accurately inform on the disease presence, stage and severity,
and gauge treatment response. The several advantages of
CMR for patients with SID are underscored by a single com-
mon denominator—CMR readouts can guide clinical man-
agement. The proposed CMR imaging protocols are presented
in Fig. 8.
Inflammatory Cardiomyopathy—T1 and T2
Mapping
Myocardial involvement in SIDs is a classical model of dif-
fuse, sustained myocardial inflammation—myocarditis—with
interchanging periods of lower and greater activity (Figs. 1
and 2). Clinical recognition of myocarditis is notoriously chal-
lenging owing to nonspecific symptoms, which in SID pa-
tients are additionally overshadowed by systemic manifesta-
tions, such as renal complications in systemic lupus erythema-
tosus (SLE) or lung involvement in systemic sarcoidosis.
Inflammatory activity is commonly at its peak within the first
decade of systemic disease. The severity of myocardial in-
volvement is well out of proportion with systemic disease
activity score and symptomatically well compensated for by
the predominately young patients [5,13,15,17,22•,27]. As
such, cardiac involvement will be detected incidentally, com-
monly by way of a raised troponin during episodes of clini-
cally manifest decompensation due to acute-on chronic in-
flammatory cardiomyopathy [32,48,49][15,22•,50•].
Thus, a focused and systematic screening in patients with
known systemic involvement, using methods that are suffi-
ciently sensitive to detect inflammation, is mandatory. T1
and T2 mapping reveal the presence of myocardial tissue
changes due to myocardial inflammation and remodelling
with fibrosis in many SID entities, including SLE, RA, sys-
temic sclerosis and cardiac sarcoidosis (Fig. 9). The two map-
ping measures are complementary in informing on the type of
cardiac involvement in SID; while native T1 is a sensitive
indicator of abnormal cardiomyopathic tissue processes, de-
tecting substrates such as myocardial inflammation, or sar-
coid, amyloid or fatty infiltration, as well as diffuse or replace-
ment fibrosis [17,36,47,51,52], native T2 is a specific
marker of myocardial oedema/inflammation [38,53,54].
Both measures are raised in the presence of active inflamma-
tion; their values rise linearly with increased severity, whereas
SAX
4CH
Cines
LGE
Churg-Strauss related DCM
Lupus-related DCM
SAX
Cines
LGE
LGE LGE
LGE
4CH 4CH
3CH
SAX
Fig. 3 Non-ischaemic dilated cardiomyopathy in SID. Upper panel:
DCM was a coincidental finding in a young SLE patient (< 20 years of
age) undergoing a pre-kidney transplant cardiac screening. CMR revealed
dilated left ventricle (indexed EDV: 152 ml/m
2
(normal range 98–62 ml/
m
2
) with severely impaired global systolic function (LVEF 20%). There
was no evidence of LGE. Biatrial dilatation indicates chronic pressure
overload due to longstanding hypertension. Native T1 was raised (at
1.5 Tesla: 1078 ms, > 4 SD [36,37]), whereas native T2 (42 ms) was
within normal range (41–49 ms) [38]. Lower panel: A 45~-year-old
patient with a known diagnosis of systemic Churg-Strauss Syndrome.
Previous history includes an ACS-like presentation with unobstructed
coronary arteries and an eosinophilic myocarditis was confirmed using
an EMB 5 years prior. CMR confirmed a dilated cardiomyopathy
(indexed LV-EDV 140 ml/m
2
(normal range 51–95 ml/m
2
), LVEF
26%), with preserved RV size and function, and LA dilatation. LGE
imaging revealed global subendocardial scarring (not limited to a single
coronary artery), also affecting RV. Native T1 was elevated at 1288 ms
(3.0 T: normal range < 1090 ms) [37], with native T2 of 36 (3.0 T: normal
range 31–39 ms)
Curr Cardiovasc Imaging Rep (2018) 11:11 Page 5 of 14 11

Fig. 4 Macrovascular coronary artery disease - ischaemia vs.
microvascular disease): Upper panel: regional myocardial ischaemia
due to obstructive coronary artery disease in a 69- year old patient with
rheumatoid arthritis (RA) yields a perfusion defect in the right coronary
artery territory (RCA: yellow arrows). Lower panel: diffuse prolonged
circumferential (sub)endothelial hypoperfusion (yellow arrows), but
preserved and rapid epicardial opacification entry (green arrows), due to
unobstructed epicardial coronary disease and inflammation-induced
endothelial dysfunction in myocardial microvasculature in a 28-year old
patient with SLE. Reproduced from Varma et al with permission [42]
B. Sarcoid paents
A. SLE paents
Fig. 5 Native T1 in discrimination between health and subclinical disease, in patients with SLE (a) and systemic sarcoidosis (b). Reproduced from [17,
22•] with permission
11 Page 6 of 14 Curr Cardiovasc Imaging Rep (2018) 11:11

drop in remission or in response to anti-inflammatory treat-
ment [50•,55]. These observations impart a marked influence
of myocardial water, as either interstitial or intracellular oede-
ma. The reactivity of both measures to this inflammatory sub-
strate makes them ideal for application in monitoring of dis-
ease activity and in guiding the anti-inflammatory treatment.
The two treatment studies revealed that the greatest change in
measures in response to anti-inflammatory treatment for sys-
temic and not cardiac systems occurs soon after initiation,
reaching a plateau thereafter, suggesting that myocardial
inflammation is reduced, however, continues at a lower level
of activity [15,22•]. This important observation is particularly
informative: whereas myocardial inflammation is a key path-
ological process, it however necessitates reassessment, moni-
toring and fine-tuning its treatment. These findings are com-
monly disproportionate relative to structural heart changes or
functional impairment, communicating the presence of in-
flammatory cardiomyopathy, which is readily detectable in a
large proportion of patients [9,17,27,28,54,56–58]. T1
mapping does not only offer diagnostic insight but also
Fig. 6 Native T1 and T2 measurements at baselineand follow up in patients receiving intensified therapy (n= 14) and those with unchanged regime (n=
21). A black line indicates trend line in the respective groups. Reproduced from Hinojar 2016 [15] with permission
Curr Cardiovasc Imaging Rep (2018) 11:11 Page 7 of 14 11

strongly relates to prognosis. A multicentre study in non-
ischaemic cardiomyopathy, a common sequel of SID-related
inflammatory cardiomyopathy [6•,59], demonstrated that the
higher the native T1 values, the more unfavourable its associ-
ation with survival, cardiac mortality and heart failure [36].
Notably, predictive association for native T1 was independent
of structural heart changes, severity of functional impairment
(LVEF) or presence of myocardial scar by LGE. Thus, by
directly linking the underlying pathological substrate and its
prognostic relevance, the information on native T1 is the sin-
gle most important measurement in patients with SID, in rec-
ognition of myocardial disease, its severity and their progno-
sis. Thus, T1 and T2 mapping may adopt a central role in
guiding the management of cardiac inflammatory involve-
ment directly, by supporting the serial assessments—which
are non-invasive, radiation-free and contrast free—allowing
to monitor disease activity and treatment efficacy and guiding
the necessary modifications in a life-long chronic disease
(Figs. 5and 6).
Distinction between Macro-
and Microvascular Coronary Disease in SID
The diagnosis of relevant coronary artery disease in patients
with presumed intermediate-high risk due to the influence of
systemic inflammation [60], with commonly less typical
symptoms, mandates functional assessment [61]. In the pre-
dominantly young and prevalently female SID population, the
choice of the diagnostic methods is relevant given the many
Fig. 7 Native T1 in prediction of all-cause mortality in patients with non-
ischaemic DCM. Kaplan-Meier curves forCMR parameters and all-cause
mortality (anative T1 (normal vs. abnormal myocardium, based on > 2
SD above the mean of the normal reference range [17]), bnative T1
ranked by 2n-times SD (ranks of SD < 2, ≥2–4, ≥4–6, ≥6 Dabir 2014
[37], cLGE present vs. absent, dLVEF < 35%. Reproduced from
Puntmann 2016 [36] with permission
11 Page 8 of 14 Curr Cardiovasc Imaging Rep (2018) 11:11

possible outcomes owing to complex pathophysiology, as
well as considerable sex differences and variation in diagnos-
tic accuracy between the methods that can be employed in
detection of relevant CAD [62,63]. To this end, myocardial
perfusion imaging with CMR offers several important advan-
tages in patients with SID: firstly, it has a higher diagnostic
and prognostic accuracy for detection of significant obstruc-
tive CAD in comparison to other non-invasive functional
methods of ischaemia testing, such as exercise treadmill or
echo testing (Fig. 4a) [64–69]. Secondly, the evidence of re-
gional hypoperfusion (of more than 4/32 myocardial seg-
ments) indicates relevant obstructive coronary artery disease,
which would prognostically benefit from coronary interven-
tion, i.e. the amount of ischaemia also filters out those patients
that actually benefit from further invasive procedures [64,
70–72]. Thirdly, myocardial perfusion CMR imaging is not
only highly sensitive for the diagnosis of ischaemia [73]but
also allows recognition of microvascular disease non-
CMR imaging protocol
Inial screening and every 3 years thereaer
T1 mapping T2 mapping LV and RV
Funcon
Myocardial
perfusion LGE
Interim monitoring of disease acvity and treatment response (6-months’ intervals)
30 min
15 min
T1 mapping T2 mapping LV and RV
Funcon
Fig. 8 Proposed CMR protocols, for screening (upper panel) and
monitoring (lower panel) of cardiac involvement in patients with SID.
Screening shall be performed at the time of diagnosis of SID. As these
patients are young, subsequent serial assessments should employ
primarily native (contrast-free) T1 and T2 mapping with CMR which is
a non-invasive and radiation-free method
, 2, p
Fixed effect model
Random effects model
Heterogeneity:
I2= 94% = 1648 < 0.01
Puntmann VO, 2017
Hromadka M, 2017
Study
Puntmann VO, 2013
Zhang Y, 2014
Hinojar R, 2016
Wu R, 2017
Ntusi NAB, 2015
Holmström M, 2017*
Holmström M, 2017*
Greulich S, 2016*
Ntusi NA, 2014
Barison A, 2015
Greulich S, 2017*
Total
474
33
24
76
24
39
29
20
61
53
19
30
29
37
Mean
1152.0
981.6
1176.0
1227.0
973.0
1173.0
1011.0
994.0
1139.0
1007.0
811.0
1258.9
988.0
SD
46.0
65.0
55.0
48.8
27.0
24.4
54.1
47.4
65.0
29.0
89.0
51.2
70.2
Experimental
Total
281
21
12
46
12
39
9
10
26
36
20
10
20
20
Mean
1056.0
963.9
1057.0
1174.7
961.0
1053.0
976.0
960.0
1052.0
958.0
790.0
1192.2
952.0
SD
27.0
32.0
23.0
95.8
18.0
152.6
13.3
32.6
34.0
20.0
84.0
32.6
27.4
Control
-200 -100 0 100 200
Mean Difference MD
52.56
55.70
96.00
17.70
119.00
52.30
12.00
120.00
35.00
34.00
87.00
49.00
21.00
66.70
36.00
95%-CI
[ 47.11; 58.01]
[ 31.73; 79.67]
[ 76.51; 115.49]
[-13.99; 49.39]
[104.96; 133.04]
[ -5.31; 109.91]
[ 1.82; 22.18]
[ 19.91; 220.09]
[ 9.90; 60.10]
[ 16.72; 51.28]
[ 66.27; 107.73]
[ 33.29; 64.71]
[-40.03; 82.03]
[ 43.22; 90.18]
[ 10.39; 61.61]
(fixed)
100.0%
--
7.8%
3.0%
15.1%
0.9%
28.6%
0.3%
4.7%
10.0%
6.9%
12.0%
0.8%
5.4%
4.5%
Weight
(random)
-
-
100.0%
8.6%
7.8%
8.8%
6.0%
8.9%
3.5%
8.3%
8.7%
8.5%
8.7%
5.7%
8.3%
8.2%
Weight
SLE
SLE
SLE
SLE
RA
RA
RA
SARC
SARC
SSC
SSC
SSC
ANCA+VASC
3T
1.5T
3T
3T
1.5T
3T
1.5T
1.5T
3T
1.5T
1.5T
3T
1.5T
*SD estimated
from interquartile
range
Fig. 9 Forest plot of studies using myocardial T1 mapping in patients with SID
Curr Cardiovasc Imaging Rep (2018) 11:11 Page 9 of 14 11

invasively, an important subentity of myocardial ischaemia,
which is highly prevalent in SID patient population. Thus,
patients will benefit from the definitive diagnosis, by either
subsequent intervention in regional macrovascular disease, or
reassurance from knowing that microvascular disease under-
lies their symptoms and may benefit from intensified tradi-
tional treatment [74,75]. Establishing correct diagnosis by
CMR will cut the commonly occurring vicious circle of the
over-investigation in SID patients and reduce the exposure to
radiation,nephrotoxic contrast agents and the procedural com-
plications [24,29,43,76,77].
Irreversible Cardiovascular Injury
and Advanced Disease
Most patients with SID will have normal cardiac volumes and
biventricular function [17,27,46,78]. Relative increase in LV
wall thickness due to myocardial inflammation precludes de-
tecting a small increase in LV volumes, only to become ap-
parent in the later stages. Thus, reduction of longitudinal myo-
cardial strain may be the earliest sign of left ventricular (LV)
functional impairment. As inflammation subsides, LV walls
will be thinned with contractile dysfunction, marking the tran-
sition to dilated cardiomyopathy. 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 [36,46,79•,80,81]. 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 [82,83]. Gross ab-
normalities, which eventually occur once disease has
progressed into advanced stages, add little beyond the confir-
mation of involvement with a poor scope for reversibility.
The presence of LGE is invariably a poor prognostic sign,
marking the burden of irreversible injury and advanced stage
of disease. The physiological mechanism of gadolinium tissue
uptake relates to the pathologically expanded extracellular
space, which is also regionally separated from the remaining
myocardial tissue with preserved myocyte membrane connec-
tions. This imaging phenomenon of brightness in the areas of
accumulated gadolinium contrast agent becomes apparent af-
ter a time lag of about 5–10 min from its administration: the
contrast agent has by then washed out from the preserved
myocardium, marking out histopathological substrates, such
as regional myocardial scar, fibrosis or extracellular oedema.
LGE is instrumental in recognition of the cardiac involvement
by way of disease-specific LGE patterns. In about a third of
patients, LGE can uncover non-ischaemic type myocardial
scar, an irreversible sequel of inflammatory injury, which
can also be unexpectedly large [9,20](Fig.10). In anti-
phospholipid syndrome or Churg-Strauss vasculitis, a suben-
docardial ‘ischaemic’-like pattern of myocardial scar is not
uncommon, yet it is a consequence of thrombo-vasculitis or
eosinophilic myocarditis, respectively, and not atherosclerosis
Case 1
Case 2
Fig. 10 LGE patterns in sarcoidosis. Representative images of myocardial scarring in cardiac involvement in systemic sarcoidosis (small scar
unexpectedly revealing the diagnosis in case 1, considerable scarring in case 2)
11 Page 10 of 14 Curr Cardiovasc Imaging Rep (2018) 11:11

[31,84–86] (Fig. 3). A classic atherothrombotic ischaemic
scar is rare in SID patients and mainly concentrated to the
older group of patients with a milder course of systemic dis-
ease and fewer cardiovascular risk factors [81,83].
Conclusion: Towards Non-invasive Clinical
Management of Myocardial Inflammation
in SID
Cardiac involvement in SIDs has a major impact on pa-
tients’outcome, yet the pathways to its recognition and
management remain poorly established [6•,82]. 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 subclin-
ical inflammation (Fig. 1): the majority of these docu-
mented cardiac manifestations, which form the knowledge
base for a high burden of CVD in SIDs, relate to ad-
vanced disease manifestations, such as heart failure and
arrhythmic presentations. Despite 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, ap-
proaches to diagnosis and management rely on relatively
insensitive, inaccurate and commonly invasive diagnostic
means. Ironically, whereas a number of major clinical tri-
als on cardiovascular inflammation in the classical cardiac
patients further substantiated the role and the need to tar-
get cardiovascular inflammation directly [87,88], similar
evidence in SID patients, where inflammation is the par-
amount physiological driver of injury and disability, is
missing [89–92].
The development of an accurate and non-invasive diagnos-
tic method for identification of myocardial inflammation is
central to the evolution of effective clinical management of
inflammatory cardiomyopathy in SIDs. To this end, CMR
with T1 and T2 mapping is the key new opportunity, allowing
to decipher myocardial inflammation directly [17,50•,53,54,
93]. Targeted and systematic CMR assessment of SID patients
shall start concomitantly with the diagnosis of SID, through a
comprehensive interdisciplinary screening programme,
allowing timely and direct anti-inflammatory cardiac care
(Figs. 1and 8). This will eventually provide a platform for
systematic assessment of clinical efficacy of CMR-guided in-
flammatory therapy; clinical trials testing such hypotheses are
needed, yet in a view of omni-present inflammatory therapy in
SID patients, large sample sizes will be required. Future sys-
tematic research shall also clarify the utility of the serological
biomarkers, to support development of interdisciplinary
screening programme to support timely delivery of cardiac
care in patients with SID.
Compliance with Ethical Standards
Conflict of Interest All authors declare that they have no conflicts of
interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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