Left Ventricular Deformation in Patients with Connective Tissue Disease: Evaluated by 3.0T Cardiac Magnetic Resonance Tissue Tracking

The aim of this study was to assess left ventricular (LV) myocardial strain in patients with connective tissue disease (CTD) and compare LV deformation between subgroups of idiopathic inflammatory myopathy (IIM) and non-IIM. Ninety-eight patients with CTD, comprising 56 with IIM and 42 with non-IIM, and 30 healthy subjects were enrolled and underwent 3.0T cardiac magnetic resonance imaging (MRI) scanning. The LV function and strain parameters were measured and assessed. Our result revealed that CTD patients had preserved LV ejection fraction (60.85%) and had significantly decreased global and regional peak strain (PS) in radial, circumferential, and longitudinal directions (all p < 0.05). IIM patients showed significantly reduced global longitudinal PS (GLPS) and longitudinal PS at apical slice, whereas all strain parameters decreased in non-IIM patients. Except GLPS and longitudinal PS at apical slice, all strain parameters in non-IIM patients were lower than those in IIM patients. By Pearson’s correlation analysis, the LV global radial and circumferential PS were correlated to N-terminal pro-brain natriuretic peptide level and LV ejection fraction in both IIM and non-IIM patients. This study indicated that CTD patients showed abnormal LV deformation despite with preserved LVEF. The impairment of LV deformation differed between IIM and non-IIM patients.

Comparison of the LV strain parameters among IIM and non-IIM patients and normal controls. In contrast to the healthy normal subjects, the magnitude of GLPS (−10.4 ± 3.2% vs.−8.6 ± 2.7%, p = 0.006) and longitudinal PS at the apical slice [−10.9 ± 4.9% vs.−8.1 ± 3.0%, p = 0.012] were significantly reduced in the IIM group, whereas the magnitude of all global and regional strain parameters in the three directions were decreased in the non-IIM group (all p < 0.05). In the non-IIM group, the magnitude of all strain parameters in the radial, circumferential, and longitudinal directions were lower than those in the IIM group, with the exception of GLPS and longitudinal PS at the apical slice (all p < 0.05) (see Table 2 and Supplementary  Fig. S1 Association between LV global strain parameters and NT-proBNP level. In the non-IIM group, GRPS was negatively associated with NT-proBNP level (r = −0.453, p = 0.005) and GCPS and GLPS were positively correlated with NT-proBNP level (r = 0.563 and 0.576, respectively; both p < 0.001). In the IIM group, NT-proBNP was correlated with GRPS (r = −0.325, p = 0.017), as well as GCPS (r = 0.351, p = 0.01) and there was no correlation between NT-proBNP and GLPS (r = 0.240, p = 0.084) (see Fig. 1). There were no significant correlations between global strain parameters in the three directions and NT-proBNP level in the healthy volunteers (all p > 0.05) (see Supplementary Fig. S2a−c).

Discussion
Cardiac involvement in patients with CTD is mostly subclinical and may lead to cardiac-related death due to myocarditis, myocardial fibrosis, valve disorders, coronary vasculitis, and pericarditis 3,6 . The underlying mechanisms of myocardial involvement in CTD are governed by autoimmunity and chronic inflammation 3 . Although the LVEF is conventionally used as a measurement of global cardiac function, this parameter has limited sensitivity for the detection of subclinical conditions 11 . Several studies have shown subclinical impairment of the myocardium in CTD patients with preserved LVEF by speckle tracking echocardiography (STE) [12][13][14] . While, there exists accumulating evidence emphasizing the role of cardiac MRI tissue tracking in overcoming the shortcomings of low tissue resolution and dependency of an acoustic window in STE for the evaluation of myocardial strain and cardiac dysfunction 15 .
In the present study, we applied cardiac MRI tissue tracking to evaluate LV myocardial systolic strain in patients with CTD and compared LV deformation between IIM and non-IIM subgroups. The main findings were: (1) patients with CTD had impaired global and regional LV systolic strain in the three directions, even though the LVEF was preserved; (2) compared with normal controls, the damaged strain in IIM patients mainly involved GLPS and longitudinal PS at the apical slice, whereas all strain values were impaired in non-IIM patients; (3) with the exception of GLPS and longitudinal PS at the apical slice, the magnitude of all strain parameters in non-IIM patients were lower than those in IIM patients; and (4) GPRS and GCPS showed correlations with LVEF and NT-proBNP level in both IIM and non-IIM patients.
The LV wall is composed of cardiomyocytes, of which the orientation continuously rotates from epicardium to endocardium 16 . Recently, CMR tissue tracking has been gradually used to quantitatively measure LV function via different strain parameters from the radial, circumferential, and longitudinal directions 8,17,18 with high sensitivity and reproducibility 19,20 . One of the findings of the present study was that, compared with healthy controls, the magnitude of global and regional PS in the three directions was decreased in CTD patients with preserved LVEF, which is consistent with STE results 12,13 . This finding may assist the explanation of the impairment of LV deformation detected by cardiac MRI tissue tracking prior to conventional LVEF in patients with CTD. Another finding was that GRPS, GCPS, and GLPS were correlated with LVEF in patients with CTD, which is similar to the previous literature reports in other diseases 7,21 .
An increasing number of studies have shown subclinical cardiac dysfunction in IIM patients detected by STE 22,23 . In our research, IIM patients with preserved LVEF were found to have impaired strain manifested as the magnitude reduction in GLPS and longitudinal PS at the apical slice, suggesting subclinical LV myocardial systolic  impairment. Previous literature has been reported that IIM patients showed impaired LV myocardial microvascular dysfunction 24,25 , and that the abnormal LV myocardial deformation was associated with microvascular dysfunction in other diseases 8,26 . Thus, we presume that the magnitude reduction in longitudinal myocardial strain of IIM patients in our present study may be related to microvascular ischemia. Analogous to our results, recent studies have reported that IIM patients with preserved LVEF have decreased global longitudinal strain 10,23 . Guerra et al. 22 described impaired longitudinal strain involved in the basal and mid-segments detected by STE, which is not consistent with our findings in the apical segment. The reasons for this discrepancy might be related to the difference in techniques used to measure LV deformation or the heterogeneity of patient populations. In addition, compared with healthy subjects, the magnitude of global and regional PS in the three directions was decreased in non-IIM patients with preserved LVEF, which is in agreement with previous reports demonstrating subclinical cardiac systolic dysfunction in other CTD besides IIM, such as SLE, RA, and SSc, as detected by STE 12,13,27 . Our research revealed that the magnitude of all strain values in non-IIM patients were lower than those in IIM patients (except for GLPS and longitudinal PS at the apical slice). Taken together, these findings support that impairment of LV deformation is different between IIM and non-IIM patients. We presume that myocardial damage manifesting as myocardial perfusion dysfunction and fibrosis differ between IIM and non-IIM. Thus, further studies are required to explore the relationships between LV deformation and the aforementioned myocardial damage detected using multi-parametric cardiac MRI, such as first-pass perfusion and late gadolinium enhancement (LGE) in IIM and non-IIM. In our present study, there was no difference between IIM patients and non-IIM patients in GLPS, and this finding might be contributed to explain GLPS was relative poor parameter (AUC:0.55; specificity: 33.93%) to differentiate IIM patients from non-IIM patients. Furthermore, the data obtained from the ROC analysis supported that the combination of GRPS and GCPS might be a better parameter than any one alone to differentiate IIM patients from non-IIM patients with a relative high sensitivity and specificity.
NT-proBNP is a biologically inactive N-terminal fragment of the active hormone BNP, which is secreted by the myocardium when stimulated by an increase in ventricular overload, ventricular wall stretchesor stress, and is a standard marker of myocardial damage 28 . Myocardial cell injury induced by persistent systemic inflammation and immune dysfunction could increase NT-proBNP level in CTD 28,29 . In the present study, NT-proBNP in non-IIM patients was higher than that in IIM patients, suggesting that the severity of myocardial damage might be different between IIM and non-IIM. Another finding demonstrated that NT-proBNP level was correlated with the global strain parameters in the three directions, which might indicate that LV global deformation is related to myocardial injury in patients with CTD. Similar to our findings, NT-proBNP has been reported to be increased in patients with CTD and correlated with subclinical cardiac disease 30 . www.nature.com/scientificreports www.nature.com/scientificreports/ The limitations of this study include the following: first, this was a retrospective and single center study, and potential center-specific bias cannot be excluded. Second, LGE data was not involved in our present study and the relationship between LV deformation and myocardial damage detected by cardiac MRI first-pass perfusion or LGE technologies is not known; thus, further studies are required to explore this. Finally, although cardiac MRI tissue tracking demonstrated high reproducibility, the accuracy needs to be further verified because of the absence of a reference standard.  Table 1 and Fig. 1  www.nature.com/scientificreports www.nature.com/scientificreports/ In conclusion, patients with CTD showed impaired LV deformation detected by cardiac MRI tissue tracking, even though they had preserved LVEF. The impairment of LV deformation was different between IIM and non-IIM patients. Early detection of subclinical impaired LV deformation may help to screen high-risk patients with CTD for early treatment.

Materials and Methods
Study population. The study cohort retrospectively enrolled 121 patients with CTD at our hospital from January 2015 to January 2019. CTD was diagnosed according to the criteria of the American College of Rheumatology or the European League Against Rheumatism, respectively. The exclusion criteria included coronary artery disease, cardiomyopathy, congenital heart disease, heart valve disease, and contraindication for cardiac MRI. Finally, 98 patients with CTD (mean age, 45.2 ± 13.2 years; 24 men) were eligible for the study, including 56 patients with IIM and 42 patients with non-IIM [13 with overlap syndrome, 5 with mixed connective tissue disease,12 with SLE, 4 with RA, 4 with Sjogren'ssyndrome,2 with undifferentiated connective tissue disease, and 2 with SSc]. Considering the variety of CTD, these patients were divided into two subgroups: the IIM group (n = 56) and the non-IIM group (n = 42). A total of 30 age-and gender-matched healthy volunteers (mean age, 45.5 ± 12.3 years; 11 men) with no history of cardiovascular or systematic disease were included as the normal controls. All participants underwent cardiac MRI scanning and were examined for the clinical marker, NT-proBNP. The study protocol was approved by the West China Hospital of Sichuan University Biomedical Research Ethics Committee and conducted in an accordance with the ethical guidelines of the Declaration of Helsinki (2013 EDITION) 31 . Informed consent was obtained from all subjects. Cardiac MRI protocol. All patients were examined using a 3.0T whole-body scanner with a 32-channel phase-array cardiovascular coil (Trio Tim; Siemens Medical Solutions, Erlangen, Germany). All participants were examined in the supine position. The breath-hold technique and a manufacturer's standard electrocardiographic gating device were used for monitoring the participant's breathing and electrocardiogram values, respectively. The continuous data were acquired during the breath-holding period. A series of 8-12 continuous cardiac MRI cine sections were acquired in the short-axis from the mitral valve level to the LV apex using a balanced steady state free precession (bSSFP) sequence (TR/TE: 39.34/1.22 ms, flip angle: 40°, slice thickness: 8 mm, field of view: 250 × 300 mm, and matrix size: 208 × 139, frequency encode direction: R-L, phase encode direction: A-P and perpendicular to the direction of blood flow). The cardiac cine series in the long-axis two-, three-, and four-chamber views were also obtained.
Cardiac MRI image analysis. Post-processing of all images was performed offline by two experienced radiologists using commercial software (cvi42, version 5.9.3; Circle Cardiovascular Imaging Inc., Calgary, AB, Canada). The LV functional parameters, including LVEDV, LVESV, LVSV, and LVEF were calculated using the aforementioned software following manual contouring of the endocardial and epicardial borders at the . Cardiac MRI tissue tracking in the four-chamber long-axis, two-chamber long-axis and short-axis cine images at the end-diastole (a-c) and end-systole (d-f). The red and green curves show the endocardial and epicardial borders, respectively; the yellow dots represent the myocardial voxel points. Abbreviations: MRI, magnetic resonance imaging.