To the best of our knowledge, this is the first study evaluating cardiac involvement in patients with CTD and preserved left ventricular ejection fraction by a comprehensive CMR approach, including LGE CMR, as well as T1 and T2 mapping techniques. The findings are as follows: 1) Patients with CTD show increased native T1, ECV, T2 and decreased post contrast T1 values compared to controls. 2) Subgroup analysis of SSc and SLE patients revealed that native T1 and T2 values seem to be higher in patients with SSc compared to patients with SLE. However, both parameters can separate between SSc/SLE patients and controls. 3) Abnormal values beyond the 95 % percentile of healthy controls might help to detect myocardial involvement in patients with CTD even in the absence of LGE.
Patient characteristics and general CMR results
Most patients were middle-aged and female, in line with previous reports [
3]. The majority of patients was non- or oligosymptomatic, and had normal ECG, underlining that the diagnosis of cardiac involvement is a challenge in CTD, Table
1. The mean LV-EF in our cohort was preserved (62 %), cardiac dimensions did not differ from controls, Table
2. LGE was present in 18 % of the CTD patients, occurring in a non-ischemic pattern in accordance with other studies [
2,
3,
20‐
22].
T1 and ECV results
We found higher native T1 values and increased ECV in our CTD population in comparison to controls, Table
2, Fig.
1a + c. Furthermore, post contrast T1 values were decreased in comparison to controls, Table
2, and Fig.
1b. Since these differences are independent of the presence of LGE, they may allow early detection of subclinical myocardial alterations in patients with CTD, as reported in other inflammatory cardiomyopathies [
23,
24].
In the SSc subgroup, differences for native T1 and ECV were even larger than in the overall CTD population, suggesting a high rate of diffuse myocardial involvement detected by T1 mapping, supporting data from Ntusi et al. [
3], who found also elevated native T1 and ECV in SSc patients. At first sight, the mapping data in this study seem to conflict with the low prevalence of LGE (12 %). However, LGE has its strengths in detecting focal processes (e.g. infarcted myocardium vs. remote myocardium), whereas in diffuse processes this technique is of limited value. Conversely, mapping techniques, which provide absolute quantitative values, rather than just visual or semi-quantitative interpretation of the images, perform well in the assessment of diffuse myocardial processes [
7]. Therefore, the T1 and ECV findings in this study might be the surrogate for the high rate of diffuse fibrosis (44–100 %) observed by endomyocardial biopsy or autopsy in SSc patients [
25,
26], and might be a useful tool not only for detection of myocardial involvement, but also for evaluation of an adequate response to immunosuppressive agents during the clinical course of the disease.
In the SLE subgroup, we observed lower T1 and ECV differences to controls than in the SSc subgroup. Consequently, although showing increased ECV and decreased post contrast T1 values compared to controls, the difference was significant only for native T1 values,
p = 0.03. This might have at least two reasons: 1) In contrast to SLE patients, autopsy studies from SSc patients revealed a high rate of diffuse fibrosis, which might be the surrogate for higher native T1 and ECV values in SSc patients [
25,
26]. 2) Our finding that native T1 seems to separate best between SLE patients and healthy controls, is supported by a recent study [
2], which identified native T1 a) as the best parameter to separate between SLE patients and controls, and b) as an independent predictor of the underlying SLE diagnosis. However, in the study by Puntmann [
2] also post contrast T1 values and ECV differed significantly to the control group. They included 33 asymptomatic SLE patients, with an activity index (SLEDAI) of 0, and observed a high LGE prevalence of 61 % (
n = 20), which is in contrast to our study (SLEDAI 16, prevalence of LGE 23 %). Another explanation for these differences might be the time duration from SLE diagnosis to CMR imaging: In the study from Puntmann et al., the average time from SLE diagnosis to imaging was 7.4 years whereas in our study almost 40 % had their CMR within the first year of SLE diagnosis. Therefore, it might be argued that the grade of diffuse fibrosis, as well as the presence of focal fibrosis detected by LGE, might increase in later stages of the disease. Since both studies found that native T1 is the most sensitive parameter to separate between SLE patients and controls, native T1 may play an important role in: a) initial diagnosis of myocardial involvement and b) the monitoring in SLE patients.
Our findings add knowledge to the potential role of T1 mapping in patients with different CTD, since this technique seems to provide more detailed tissue characterization than LGE alone. This might have clinical implications for the assessment of disease activity, and monitoring of the response to immunosuppressive medication in CTD patients. Moreover, since T1 and ECV values in patients with ECG abnormalities did not differ to the values of patients with normal ECG, the presence of ECG abnormalities alone may be of limited diagnostic value for detecting myocardial involvement in CTD patients.
T2 results
In contrast to T1 mapping, myocardial T2 values correlate closely with free tissue water content [
27,
28], predisposing them for the assessment of active myocardial inflammation in systemic disorders such as CTD. Newer T2 mapping sequences provide objective and robust data [
8,
29], and will most likely replace previously described T2-weighted sequences [
7].
As expected in systemic inflammatory disorders such as CTD, median myocardial T2 values were significantly higher than in controls, suggesting myocardial involvement due to systemic inflammation, Table
2, Fig.
1d. Of note, T2 performs even better than native T1 to separate controls from CTD patients (
p < 0.001,
p = 0.001, respectively). This difference remains significant by dividing the CTD population in a LGE-positive and a LGE-negative group, underlining the additional value of T2 mapping in comparison to the performance of LGE CMR alone.
For the SSc subgroup, we found only studies in the literature that used T2-weighted images for the assessment of inflammation instead of newer T2 mapping techniques [
3,
30]. We filled this gap and found higher T2 values both than controls (
p < 0.001), and patients with SLE (
p = 0.001), suggesting a high grade of myocardial inflammation, possibly representing active disease, in SSc patients. The occurrence of both myocardial inflammation and diffuse fibrosis is a well-known finding in these patients [
3]. Thus, a comprehensive CMR approach including LGE, T1 and T2 mapping seems a reasonable approach to evaluate both chronic and active stages of the disease in SSc patients.
Our data are also supported by a recent study [
31], which reported elevated T2 values in SLE patients compared to controls. However, their T2 values were higher in SLE patients and controls as compared to the values in this study, which might have the following reasons: 1) Different patient populations: our patients were younger; 2) different grades of inflammation due to different immunosuppressive treatment regimen: 77 % of our patients were on steroids vs. only 17 % in the latter study. 3) Differences in the T2 mapping sequence and map analysis software. Therefore, as long as there are no consistent mapping sequences, each institution should create its individualized normal values [
12]. Of note, T2 values of our control group were in line with the results of other groups [
32].
Since increased T2 values are supposed to represent potentially reversible processes [
31], T2 mapping might play an important role as a quantitative biomarker, which might serve as surrogate for response or failure of immunosuppressive agents.
As shown above for T1 values, T2 values in patients with normal vs. abnormal ECG did not differ significantly, underlining the need for further detailed tissue characterization for the detection of myocardial involvement in CTD.
Values above the 95 % percentile of normal
Despite highly significant differences in T1 and T2 values between the CTD population and controls, there is still some overlap in values, hampering the diagnosis of myocardial involvement in the individual CTD patient, also see Fig.
1. Therefore, we used the 95 % percentile of our control group as a threshold for definite abnormal values in patients with CTD.
The majority of abnormal values were reported for T2 (
n = 15), and native T1 (
n = 10), suggesting to be the most promising parameters for potential detection of myocardial involvement. Of note, 87 % of these patients with elevated T2 values, and 90 % of the patients with elevated T1 native values, were LGE-negative, see Fig.
4.
In the SSc and SLE subgroups we found comparable results, with native T1 and T2 as most frequent parameters above the 95 % percentile of normal, and a high rate of LGE-negative patients, see Fig.
5. These findings underline the additional benefit of the newer mapping techniques compared to LGE imaging alone.
Clinical implications
In this study, we could demonstrate that mapping sequences in addition to LGE-CMR might be useful for the detection of myocardial involvement in patients with CTD. Patients with CTD show higher T1, ECV, and T2 values compared to healthy controls. These findings are independent of the presence of LGE. Furthermore, subgroup analysis in SSc and SLE patients revealed that native T1 mapping and T2 mapping are the best parameters to separate between normal subjects and patients. This could be confirmed among patients with values higher than the 95 % percentile of controls, suggesting a combination of both fibrosis and inflammation in CTD patients.
Despite potential life-threatening complications by myocardial involvement of CTD, many patients will present with nonspecific symptoms, normal ECG, and preserved LV-EF. Thus, a comprehensive CMR approach may be of future clinical importance not only for detection of myocardial involvement but also for response to treatment. Nevertheless, larger randomized trials are warranted to investigate the diagnostic and prognostic value of abnormal mapping findings, before these sequences can be implemented in the clinical routine.
Limitations
Several potential limitations need to be addressed. Due to the single center setting, potential center-specific bias cannot be excluded. However, since most mapping sequences are vendor and center specific, there is still a lack of established normal values and thresholds, so preferably centers should establish their own normal values and thresholds upon healthy controls, as suggested by current recommendations [
12].
The overall CTD group, and in particular the SSc and SLE subgroups are small, but comparable in size to most of the studies in the current literature dealing with CTD. Furthermore, despite the relatively small numbers of patients, significant differences in the mapping parameters were measured compared to controls.
Measuring global myocardial T1 or T2 values in a single mid-ventricular slice might overlook focal processes. However, this approach is common practice [
33,
34], less subjective and might be even better comparable to follow-up exams. Moreover, for comparing different CMR techniques (native T1, post contrast T1, ECV, T2), it is fundamental that measurements are made in matching locations.
Endomyocardial biopsy was not routinely performed. However, it is well known that EMB has several limitations, e.g. invasiveness, sampling error, lowering its diagnostic benefit. Furthermore, in oligosymptomatic patients with preserved LV-EF, this would be a rather unethical approach, and not in line with current guidelines [
35].
Comparing mapping results to cardiac biomarkers would have been of interest, however this was not intention of our study, and should be investigated by further studies.