CMR feature tracking in cardiac asymptomatic systemic sclerosis: Clinical implications
CMR feature tracking in cardiac asymptomatic systemic sclerosis: Clinical implications
Konstantinos Bratis 0 2
Anthony Lindholm 2
Roger Hesselstrand 2
H?kan Arheden 2
Georgia Karabela 2
Efthymios Stavropoulos 2
Gikas Katsifis 2
Genovefa Kolovou 0 2
George D. Kitas 2
Petros P. Sfikakis 1 2
Loukia Koutsogeorgopoulou 2
Sophie Mavrogeni 0 2
Ellen Ostenfeld 2
0 CMR Unit, Onassis Cardiac Surgery Centre , Athens , Greece , 2 Department of Clinical Sciences, Clinical Physiology, Ska?ne University Hospital, Lund University, Lund, Sweden, 3 Department of Clinical Sciences, Rheumatology, Ska?ne University Hospital, Lund University, Lund, Sweden, 4 Naval Hospital , Athens , Greece , 5 Arthritis Research UK Epidemiology Unit, University of Manchester , Manchester , United Kingdom
1 First Department of Propeudeutic and Internal Medicine, Laikon Hospital, Athens University Medical School , Athens , Greece , 7 Pathophysiology Department, Laikon Hospital , Athens , Greece
2 Editor: Giuseppina Novo, University of Palermo , ITALY
Data Availability Statement: All relevant data are
within the manuscript.
Funding: This work was supported by Sk?ne
University Hospital, Region of Sk?ne, Southern
Healthcare Region of Sweden and Lund University.
The funders had no role in study design, data
collection and analysis, decision to publish, or
preparation of the manuscript.
Competing interests: The authors have declared
that no competing interests exist.
Impaired myocardial deformation has been sporadically described in cardiac asymptomatic
systemic sclerosis (SSc). We aimed to study myocardial deformation indices in cardiac
asymptomatic SSc patients using cardiac magnetic resonance feature tracking (CMR-FT)
and correlate these findings to the phenotypic and autoimmune background.
Fifty-four cardiac asymptomatic SSc patients (44 females, 56?13 years), with normal routine
cardiac assessment and CMR evaluation, including cine and late gadolinium enhancement
(LGE) images, were included. SSc patients were compared to 21 sex- and age- matched
healthy controls (17 females; 54?19 years). For CMR-FT analysis, a mid-ventricular slice for
LV peak systolic radial and circumferential strain and a 4-chamber view for LV/RV peak
systolic longitudinal strain were used.
Twenty-four patients had diffuse cutaneous SSc and 30 limited cutaneous SSc. Thirteen
patients had digital ulcers. Median disease duration was 3.6 years. LV ejection fraction was
higher in SSc patients compared to controls (62?6% vs. 59?5%, p = 0.01). Four patients
had no LGE examination; in the remaining patients LGE was absent in 74%, while 18%
had RV insertion fibrosis and 8% evidence of subendocardial infarction. LV longitudinal
strain differed in those with insertion fibrosis (-18.0%) and infarction (-16.7%) compared to
no fibrosis (-20.3%, p = 0.04). Patients with SSc had lower RV longitudinal strain and strain
rate compared to controls (p<0.001 and p = 0.01, respectively). All other strain and strain
rate measurements were non-significant between patients and controls.
In cardiac asymptomatic SSc patients with normal routine functional indices, CMR-FT
identifies subclinical presence of insertion fibrosis and/or myocardial infarction by impaired LV
longitudinal strain. RV derived longitudinal indices were impaired in the patient group. CMR
FT indices did not correlate to the patients? phenotypic and autoimmune features.
The heart is a major target organ in systemic sclerosis (SSc), appearing to be involved in 12?
80% of autopsy studies [
], although the involvement is often clinically silent [
] and is
recognized only in 15?25% [
]. Myocardial disease is complex and dynamic and includes
myositis, characterized by immune-mediated myopericardial inflammation [
] and fibrosis [
] predisposing to cardiac dysfunction and failure, coronary
artery disease, conduction system abnormalities and pericardial disease [
]. All subtypes of
SSc are at risk for significant heart disease, but patients with rapidly evolving diffuse skin
] as well as those with underlying skeletal muscle disease [
] are prone to develop
severe cardiomyopathy. Cardiac involvement carries an ominous prognosis, irrespective of the
clinical presentation . Early detection allows to timely start an immunosuppressive
treatment and possibly prevent cardiac damage progression [
Cardiovascular magnetic resonance (CMR) is an accurate method for non-invasive,
nonradiating assessment of ventricular volumes, function, myocardial perfusion as well as tissue
]. While ejection fraction is of prognostic value, it is a crude measure of
subtle myocardial changes. Feature tracking derived from CMR cine images (CMR-FT) offers
quantitative assessment of the myocardial deformation, beyond global assessment with
ejection fraction and before other recognized markers [
In the setting of SSc, there is only limited data [
] examining CMR derived left (LV) and
right ventricular (RV) deformation indices in patients with SSc compared to healthy controls
and their relationship to clinical subsets (diffuse cutaneous SSc (dcSSc) and limited cutaneous
SSc (lcSSc)) and other disease features (presence of digital ulcers, disease duration, antibody
subset). The aims of this study were 1) to investigate if LV longitudinal, radial and
circumferential as well as RV longitudinal strain differ in cardiac asymptomatic SSc patients with
preserved ejection fraction and normal estimated pulmonary pressure compared to healthy
controls, 2) to correlate the LV and RV deformation indices to clinical subsets (lcSSc vs
dcSSc) and other disease characteristics (digital ulcers, autoimmune profile, disease duration,
unknown myocardial fibrosis) and assess its potential clinical value.
2. Materials and methods
2.1. Patients and controls
The study was conducted at Sk?ne University Hospital, Lund, Sweden and Onassis Cardiac
Surgery Centre, Athens, Greece and patients were included from both hospitals. Patients
fulfilling the American College of Rheumatology criteria [
] and/or LeRoy?s classification
criteria for the diagnosis of SSc [
], who were prospectively included in prior studies from
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our groups [
17, 23, 24
] and had undergone a CMR exam were retrospectively included and
analysed provided they had normal routine cardiac assessment and no cardiac symptoms.
Exclusion criteria were known heart disease, renal failure, pulmonary hypertension and
contraindications to CMR.
Medical records were reviewed to collect clinical characteristics of the patients. Detailed
history, physical examination, routine laboratory investigations, autoimmune screening as well
as screening for atherosclerotic disease risk factors were assessed in all patients. For subgroup
analyses, patients were divided based on the observation time from SSc diagnosis to CMR
examination (disease duration), skin involvement (lcSSc vs dcSSc), presence of digital ulcers
and autoimmune profile [anti centromerantibodies (ACA), anti-nuclear antibodies (ANA),
anti RNA polymerase III antibodies (ARA), anti-topoisomerase I antibodies (ATA))]. SSc
patients were compared with sex-matched healthy controls that underwent cine CMR
evaluation during the same period. Controls were prospectively enrolled in previous study from the
Lund group [
] and were matched with the patient population for sex and age, as LV strain
with CMR has been shown to be sex dependent [
]. Controls were checked for and had no
cardiac morbidities, medical history or medication and were examined by clinicians before
their study enrollment.
This study was approved by the ethics committees of Sk?ne University Hospital, Lund,
Sweden and Onassis Cardiac Surgery Centre, Athens, Greece in accordance with the ethical
guidelines of the 1975 Declaration of Helsinki. Informed written consent was obtained from
patients and healthy controls.
2.2. CMR protocol
CMR was performed on a 1.5 Tesla scanner using ECG-triggered cine steady-state free
precession breath-hold cine long-axis planes and sequential 8 mm short-axis slices including the
atrioventricular ring to the apex to assess ventricular function. Typical image parameters were:
echo time (TE) 1.4?1.6, repetition time (TR) 2.8?3.2 ms, flip angle 60? and gap 0 mm (Achieva,
Philips Medical Healthcare, Best, the Netherlands), 2 mm (Aera, Siemens, Erlangen, Germany)
and 3 mm (GE hdxt 1.5 T, version 16, GE Healthcare, Milwaukee, WI, USA).
To assess for fibrosis, late gadolinium enhanced (LGE) images were acquired 10?15
minutes after intravenous administration of gadolinium-DOTA (Dotarem, Guerbet, Roissy,
France; 0.2mmol/kg) in identical short-axis planes using an inversion-recovery gradient echo
sequence for fibrosis detection. Inversion times were adjusted to null normal myocardium.
2.3. CMR image analysis
CMR studies were analysed with Circle cmr42 5.3.4 Tissue-Tracking Plugin (Circle
Cardiovascular Imaging Inc., Calgary, AB, Canada) in a random order blinded to the patient clinical
characteristics (A.L.). Cine short axis was used to evaluate LV and RV ejection fractions (EF).
Analyses of myocardial deformation from two-dimensional strain and strain rate data were
performed using feature-tracking imaging. Peak systolic LV and RV longitudinal myocardial
deformation were measured in the left 4-chamber view (Fig 1). LV longitudinal deformation
was the average of 7 segments, while the RV deformation was the average of RV free wall
alone. Peak systolic LV radial and circumferential deformation indices were measured in LV
short axis view at the mid ventricular level and were expressed as the average of six segments.
The intrinsically negative measured data were converted to absolute values. In case of
misalignment, an experienced observer acted as a blinded independent adjudicator (E.O.). For
interobserver variability second observer (K.B.) blinded to prior data analyzed deformation
indices on 15 individuals (10 patients and 5 controls). The evaluation of scar tissue was
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Fig 1. Example of delineations in one slice from a short axis stack (left) and 4-chamber long axis view (right). Green line represents left
ventricle epicardial border, red line represents left ventricular endocardial border. Blue circle represents the insertion point in the short axis
between the right and left ventricle and blue lines represent left ventricle atrioventricular plane and ventricular axis to the apex. Yellow line
represents right ventricle endocardial border, light blue line represents right ventricle epicardial border and the brown line represents the right
ventricle atrioventricular plane and ventricular axis to the apex.
performed visually from the late gadolinium enhancement images (E.O.) and was categorized
as absent LGE, fibrosis at RV insertion and subendocardial or transmural infarction.
2.4. Estimation of pulmonary pressure
Echocardiography was performed on clinical indication and/or as screening for pulmonary
arterial hypertension. Pulmonary pressure was estimated from trans-tricuspid regurgitation
with maximum velocity (TRVmax). TRVmax 2.8 m/s was considered normal estimated
pulmonary pressure, while TRVmax > 2.8 m/s giving rise to suspected elevated pressure [
Patients with suspected elevated pressure had invasive right heart catheterisation performed
by clinical indication. Mean pulmonary arterial pressure 25 mmHg was considered elevated
] and patients with increased pulmonary pressure were not included.
2.5. Statistical analysis
All data are reported as mean ? SD. Statistical analysis was performed using SPSS software
(SPSS Inc., Chicago, IL, USA, version 23.0). Correlation analysis was assessed using Pearson?s
correlation. Volumetric measurements were normalized to the body surface area. Chi-square
and unpaired student t tests were used to compare groups. ANOVA was used to test
differences among groups. Mean ? SD was calculated to study the variability of the measurements.
Inter-observer variability was assessed using intra class correlation coefficient. Results with a
p-value of < 0.05 were considered statistically significant.
3.1. Patient and controls
Fifty-four cardiac asymptomatic SSc patients (44 females, aged 56 ? 13 years) with no known
cardiac involvement were retrospectively enrolled into the study. Twenty-one age- and
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Expressed as mean?SD or absolute numbers with percentage in parenthesis.
Control = Healthy adult volunteers; SSc = Systemic sclerosis; BSA = Body surface area; LV mass = Left ventricular mass; CMR = Cardiac magnetic resonance;
mRSS = Modified Rodnan skin score; COPD = Chronic obstructive pulmonary disease; IHD = Ischemic heart disease; SSc-duration in years; ACE/ARB = Ace inhibitor/
Angiotensin II blocker; CCB = Calcium channel blocker; BB = Beta-blocker; ERA = Endothelin-receptor antagonists; PDEI5 = Phosphodiesterase type 5 inhibitor;
NSAID = Non-steroidal anti-inflammatory drugs, n/a = not applicable
gender- matched healthy controls were used for comparison [
]. Demographic characteristics
are shown in Table 1. CMR functional characteristics of the included patients and control
subjects are shown in Table 2.
Twenty-four patients were diagnosed as having dcSSc and 30 as having lcSSc. Digital ulcers
were registered on 13 patients and 41 did not have digital ulcers. Nineteen patients had anti
centromere antibodies (ACA), 18 had anti topoisomerase I antibodies (ATA), 4 had anti RNA
polymerase III antibodies (ARA), 10 had anti-nuclear antibodies without ACA, ARA or ATA
(ANA+) and 3 were ANA-negative (ANA-). Patients had mean disease duration (time of
observation from SSc diagnosis to CMR examination) of 43 months (range 6.6?311 months).
Four patients had LGE pattern consistent with myocardial infarction (2 had subendocardial
and 2 had transmural infarction) of which only one had prior suspected ischemic heart disease
and 9 had fibrosis at RV insertion, leaving 37 patients without visually localized fibrosis and
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Limited SSc P-valueB No Digital Ulcer Digital Ulcer P-valueC
(n = 30) (n = 41) (n = 13)
Strain is measured in (%), Strain rate is measured in (1/s) expressed in mean?SD.
A: controls versus all SSc,
B: diffuse versus limited cutaneous SSc,
C: without versus with digital ulcers.
D: Two controls had inadequate image acquisition for radial and circumferential tracking,
E: Two patients had artefacts,
F: 7 had no time data for strain rate analysis in short axis images,
G: Five patients had not time data for strain rate analysis in 4-chamber view,
H: One control had inadequate tracking for RV strain analysis.
Control = Healthy adult volunteers; SSc = Systemic sclerosis; LVEF = Left ventricular ejection fraction; LVEDV = Left ventricular end diastolic volume; LVESV = Left
ventricular end systolic volume; LVSV = Left ventricular stroke volume; RVEF = Right ventricular ejection fraction; RVEDV = Right ventricular end diastolic volume;
RVESV = Right ventricular end systolic volume; RVSV = Right ventricular stroke volume
scar. Four patients had no gadolinium administration due to impaired kidney function
(n = 1), anxiety/claustrophobia ending the examination (n = 2) or declining to receive
gadolinium (n = 1).
3.2. CMR-FT results
3.2.1. Myocardial deformation analysis in SSc patients compared to controls. Patients
with SSc had lower RV longitudinal strain and strain rate compared to controls (p<0.001
and p = 0.01, respectively). All other strain and strain rate measurements were non-significant
between patients and controls (Table 2).
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When evaluating skin involvement, all strain and strain rate measurements were
non-significant between patients with lcSSc, dcSSc or healthy controls (Table 2).
When evaluating severe microvascular involvement of the skin, all strain measurements,
except LV mid circumferential strain (p = 0.02), were non-significant between patients with or
without digital ulcers (Table 2).
LV longitudinal strain was lower in patients with insertion fibrosis (-18.0%) and even lower
in patients with infarction (-16.6%) compared to those without fibrosis (-20.3%, p = 0.04
among the groups). LVEF, LV radial and circumferential strain as well as RV longitudinal
strain did not differ among the groups. However, RVEF was lower in patients with fibrosis and
infarction (Table 3).
In disease duration correlation analysis, all correlations between disease duration and strain
and strain rate measurements were non-significant (LV longitudinal strain, p = 0.8; RV
longitudinal strain, p = 0.2; LV mid radial strain, p = 0.7; LV mid circumferential strain, p = 0.6;
LV longitudinal strain rate, p = 0.7; LV mid radial strain rate, p = 0.3; LV mid circumferential
strain rate, p = 0.5).
All strain and strain rate measurement, except LV longitudinal strain rate (p = 0.04), were
non-significant when comparing groups of autoantibodies ACA, ARA, ATA, ANA+ or ANA
(LV longitudinal strain, p = 0.9; LV mid radial strain, p = 0.3; LV mid circumferential strain,
p = 0.08; LV mid radial strain rate, p = 0.6; LV mid circumferential strain rate, p = 0.4; RV
longitudinal strain, p = 0.1).
3.2.2. Variability. Intra-class correlation in inter-observer variability was <0.5 for LV
longitudinal strain, RV longitudinal strain, LV radial strain and LV circumferential strain.
In this CMR study, early cardiac involvement in cardiac asymptomatic SSc patients was
documented in the RV but not in the LV. SSc patients had smaller LV/RV volumes as well as higher
LVEF, but no difference in radial, circumferential or longitudinal indices, compared with
ageand gender-matched healthy controls. Thirteen out of fifty SSc patients had insertion fibrosis
and/or infarction, detected due to lower LV longitudinal strain, compared with those without.
Finally, LV circumferential strain and LVEF were higher in SSc without, compared with those
with digital ulcers.
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The finding of smaller LV and RV volumes and higher LVEF could be related to heart
rate. Interestingly, LV mass was not significantly different between patients and controls. SSc
patients have higher heart rate than normal controls, and autonomic dysfunction with altered
diastolic function and cardiac remodeling in SSc has been suggested [
vasoactive calcium channel blockers (such as the often used Nifedipine) can induce increased heart
rate as a reflection of the sympathetic nerve system of vasodilatation . With 50% of patients
having calcium channel blockers, in our study, both SSc in itself and calcium channel blockers
can cause higher heart rate. A higher heart rate decreases the diastolic filling, and this could
affect the volumes and function . Lastly, diffuse fibrosis could stiffen the myocardium and
leads to decrease the ventricular volumes, leading to increased LVEF. In a recent study by
Hroma?dka et al. on SSc patients  the conventional echocardiography parameters were similar
in SSc patients and controls. However, the global longitudinal peak systolic strain (GLPS) was
lower in SSc patients compared to controls and correlated negatively with native T1 (30). In
our study, ventricular volumes and detection of local fibrosis were in parity with the
echocardiographic results. However, in the latter study no subclinical infarction was reported.
Global longitudinal strain has an important role in identifying early myocardial dysfunction
in patients with non-ischemic cardiomyopathies [33, 34]. However, in the majority of our
patients left ventricular indices were not different in SSc compared to controls. This is
potentially due to the selection of asymptomatic patients in which the purpose of our study was
to find subclinical manifestations. Our results were in agreement with recent data showing
subclinical CMR-derived myocardial deformation abnormalities in SSc patients, due to
underlying fibrosis or infarction, as assessed by LGE [
], as well as parametric imaging .
Furthermore, LGE was significantly associated with circumferential and radial strain that is also
in agreement with our results. The early detection of cardiac involvement in SSc could allow
timely redirection of the management of these patients and potentially prevent the progression
to cardiac damage with improved quality of life and longevity, underscoring the potential
value of CMR-FT in identifying cardiac involvement in this cohort of patients.
Right ventricular deformation indices were significantly impaired in the patients? group.
SSc patients are prone to develop pulmonary hypertension and early RV involvement should
always be suspected in this population. Our results are in agreement with previous
echocardiography derived ones identifying early-stage impaired myocardial deformation.  Defining
early markers of impaired RV function is crucial and may constitute a potential target for early
We aimed further to examine the potential correlation of myocardial deformation to the
underlying SSc clinical status and autoimmune profile. It has been documented that cardiac
manifestations occur earlier and more frequently in patients affected by dcSSc than with lcSSc
. Patients with lcSSc or dcSSc are characterized by clinically evident inflammatory and
fibrotic processes of the skin, especially those with ARA. These mechanisms also play a major
role in cardiac involvement leading to various clinical manifestations including heart failure,
arrhythmias and pulmonary hypertension. Patients with dcSSc are at higher risk to develop
cardiac involvement than those with lcSSc [38, 39]. However, in our study, the lack of
differences between patients with lcSSc and dcSSc are consistent with a previous study in which
cardiac symptoms were not found to be significantly different with the use of echocardiography
derived indices between the two subtypes .
There were no major differences in strain among patients with different autoantibody
profile. So far, there has been conflicting data in the literature whether strain is altered in
patients with different phenotypes of autoantibodies [36, 39, 41]. Further large-scale research
is required to offer more insight on the relative myocardial involvement in these subgroups of
patients. After all, in the present study, the subgroups were rather small.
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From a technical perspective, our strain measurements were expressed as the fractional
change in the length (as a percentage) from the resting state (end diastole) to the state
following myocardial contraction . Strain analysis using this feature tracking method  is as
feasible for the assessment of non-tagged SSFP cine CMR as for tagging CMR, indicating a
unique new approach for comprehensive clinical assessment of regional cardiac function .
Tracking techniques have been reported more robust and reproducible  for global rather
than regional values [
Both echocardiography and CMR currently offer reproducible measurements of global
strain values that can be applied in different clinical scenarios to assess LV and RV function
]. CMR has an established and continuously expanding role in tissue characterization and
is the modality of choice for accurate evaluation of global function using volumetric
assessment. The additional value of myocardial deformation information beyond direct tissue
characterization remains to be evaluated. A reliable segmental analysis is expected to render the
technique clinically meaningful.
5. Limitations of the study
Limitations of the study were:
1. The use of multiple scanners and effects on variability of CMR measurements. From
echocardiography, examining the same patient with two echo machines from different vendors
can generate different strain values even when images are interpreted with the same
] and analysis software from different vendors can generate different strain values
even from the same image data set. [
] However, we used the same software and
multivendor comparison for CMR strain analysis are not available yet. Multicenter studies with
multivendor assessment of LGE and myocardial at risk has been published [
] why we
consider the assessment of fibrosis from three vendors as a minor limitation
2. Our study included mainly long-term SSc cardiac asymptomatic patients with a median
time of 3.6 years from diagnosis. Therefore, part of the included patients had already
received potentially cardiotoxic disease-modifying agents.
3. Our CMR protocol included only functional assessment as well as visual detection of focal
replacement fibrosis. Parametric imaging, which is currently the most sensitive index for
detection of diffuse myocardial fibrosis, irrespective of LGE, was not included in the
protocol. Perfusion imaging has been the subject of previous studies by some of the authors. [
4. The sample size of the patient group is small but comparable to number of patients
traditionally used in similar studies, given the rare nature of the entity. The control group was
matched with the patient population for sex and age, although LV strain with CMR has
been shown to be only sex dependent, in order to achieve the maximal accordance between
the two groups.
A comprehensive biventricular myocardial deformation study with CMR feature tracking and
LGE reveals early subclinical cardiac involvement in cardiac asymptomatic SSc with normal
routine cardiac evaluation. CMR-FT contributed to differentiate the patients with silent
myocardial necrosis as well as identified early RV involvement. The clinical significance of CMR
deformation abnormalities for outcome and treatment goals remains to be elucidated through
multicenter longitudinal studies.
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Conceptualization: Konstantinos Bratis, H?kan Arheden, Genovefa Kolovou, Sophie
Mavrogeni, Ellen Ostenfeld.
Data curation: Roger Hesselstrand, Georgia Karabela, Efthymios Stavropoulos, Gikas Katsifis,
George D. Kitas, Petros P. Sfikakis, Loukia Koutsogeorgopoulou.
Formal analysis: Konstantinos Bratis, Anthony Lindholm, Ellen Ostenfeld.
Writing ? original draft: Konstantinos Bratis.
Writing ? review & editing: Sophie Mavrogeni, Ellen Ostenfeld.
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