Potential Clinical Utility of a Free-Breathing Cardiac Magnetic Resonance Imaging Protocol at 3T

Background It is hard for patients with impaired breath-holding (BH) capacity to receive conventional cardiac magnetic resonance (CCMR) imaging. Purpose To explore the clinical utility of a free-breathing (FB) CMR (FCMR) imaging protocol at 3.0T. Methods 54 selected patients with suspected heart disease were prospectively enrolled. A total of 30 patients with good BH underwent CCMR protocols rst and then FCMR imaging protocols. For other 24 patients with bad BH, CCMR protocols were aborted due to limited BH capacity of patients that led to non-diagnostic image quality (IQ), and the study was nished with FCMR protocols. CCMR included segmented cine and late gadolinium enhancement (LGE) images acquired under BH. FCMR included compressed sensing (CS) accelerated, single-shot cine and motion-corrected (MOCO) single-shot LGE images acquired under FB. IQ of both protocols was evaluated based on a ve-point Likert scale. The imaging time, the left ventricular function(LVF), scar presence/absence, and IQ were compared between CCMR and FCMR protocols. <0.001]. No signicant differences were found in LVF, and LGE presence(all P>0.05). The 24 patients with limited BH capabilities had inconclusive results with the CCMR protocol, but denitive diagnoses were made with the FCMR protocol. Conclusions FCMR could be used as an alternative scanning protocol in patients with BH impairments, making CMR imaging more widely available also for vulnerable patients.


Introduction
Cardiovascular magnetic resonance (CMR) imaging has become an essential tool for the non-invasive examination of the heart. It has been used for the diagnosis, risk strati cation, and prognosis of cardiac diseases [1,2]. Cine and late gadolinium enhancement (LGE) imaging are routinely included in the conventional cardiovascular magnetic resonance (CCMR) protocols in our center. Data acquisitions are typically performed with breath-holding (BH). While they work well in patients that are capable of holding their breath during image acquisition, such CCMR protocols remain challenging in patients with compromised BH capacities. In addition, the relatively long imaging time hinders the e ciency and throughput at a busy medical center like ours where there is a need to scan over 30 cardiac patients per MRI system per day.
Real-time compressed sensing (CS) cine has been proved to be able to obtain high-quality images for evaluating cardiac function [3][4][5][6][7]. Motion corrected (MOCO) single-shot LGE imaging techniques can also produce high-quality images without BH to detect brotic myocardial scars [8][9]. The novelty in this work is that both methods (CS cine and MOCO-LGE) are in corporated for a comprehensive FB CMR study. The feasibility and potential clinical utility of the proposed protocol were evaluated in patients that were unable to hold their breath during CMR imaging.

Subject enrollment
After the institutional review board approval was granted, adult patients scheduled for CCMR imaging were prospectively recruited for this study. The inclusion criteria were as follows: in-patient at our hospital scheduled for contrast-enhanced CMR examination, a glomerular ltration rate of ≥30 mL/min per 1.7m 2 , and no contraindications for CMR imaging. All patients who received FCMR protocols signed informed consent.
The Cmr Imaging Protocol CCMR and FCMR scans were performed on a 3 Tesla (T) clinical magnetic resonance imaging (MRI) scanner (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). The system was equipped with an 18-element body array coil and a 32-element spine array coil. Key sequences for the CCMR included: (1) BH-cine imaging with segmented, balanced steady-state free precession (bSSFP) readout; (2) BH-LGE sequence for viability imaging under breath-hold using segmented, fast low-angle shot (FLASH) readout and phase-sensitive inversion recovery (PSIR) reconstruction. The primary FCMR protocols included: (1) Single-shot FB-CS-cine imaging with bSSFP readout, featuring a two-dimensional sparse data sampling and iterative reconstruction (SSIR); and (2) FB-MOCO-LGE employs non-rigid motion-correction and averaging of multiple single-shot SSFP images with PSIR reconstruction [4]. The BH-cine, FB-CS-cine, BH- LGE, and FB-MOCO-LGE protocols comprised separate 2-, 3-, and 4-chamber long-axis (LAX) acquisitions, and a short-axis (SAX) stack covering the entire left ventricle (LV). All scans were started from running BH CCMR protocols and the process was as follows: (1) If a patient could not hold breath which subsequently led to severe imaging artifacts, CCMR protocols were stopped and FCMR protocols were employed to nish the study. (2) In a cohort of 30 patients that CCMR protocols were successfully nished, FCMR protocols were also added to compare image acquisition times, the left ventricular function(LVF), scar presence/absence, and image quality (IQ). Intravenous gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) contrast agent was administered at a dose of 0.2 ml/kg of body weight. For all exams, the contrast agent was administered to each patient in one injection. The CMR protocol work ows is illustrated in Fig. 1. Detailed information regarding the sequence parameters of both protocols is shown in Table 1. Both protocols were conducted using semi-automated cardiac day optimizing throughput (DOT) engine software including AutoAlign feature to automatically prescribe the 2-, 3-, and 4-chamber views as well as the short axis stack [10]. Scan parameters like trigger delay were automatically adapted to patient physiology such as patient heart rate.

Left ventricular function (LVF)
LVF measurements were assessed with cmr42 software. Endocardial and epicardial contours were automatically delineated on the short-axis cine images using the cmr42 software and manually adjusted as needed [11]. Papillary muscles and trabeculations of the left ventricle (LV) were included in the ventricular cavity volume measurements. Ejection fraction (EF), end-diastolic and end-systolic volumes (EDV and ESV), stroke volume (SV), and LV end-diastolic mass (LVEDM) measurements were accessed from the cine images acquired in both protocols, and the consistency of measurements between both protocols was analyzed by using linear regression analyses and Bland-Altman plots.

Late gadolinium enhancement detection
If LGE involves the subendocardial distribution of coronary artery, it can be identi ed as ischemic LGE type; otherwise, it can be identi ed as non-ischemic LGE [12,13].

Statistical analyses
Statistical analyses were performed using dedicated SPSS (version 20.0, SPSS Inc., Chicago, USA) and MedCalc10.0 (MedCalc Software, Ostend, Belgium) software. Continuous data were checked for normality using the Shapiro-Wilk test and presented as the mean ± standard deviation or median (interquartile range, Q1-Q3), and compared using the T test or Mann-Whitney test. Linear regression analyses were used to evaluate the consistency of quantitative data, correlation coe cients were expressed as R2, and Bland-Altman plots analyzed LVF biases between the FB-CS-cine and BH-cine images. P <0.05 was considered statistically signi cant.

Patient characteristics
A total of 54 patients who underwent CMR imaging at our hospital were prospectively enrolled for this study.  The BH-LGE and FB-MOCO-LGE measurements could detect LGEs similarly, including 4 cases with ischemic LGEs, 15 cases with non-ischemic LGEs, and 11 cases with negative results.

CMR Findings
Of those 30 patients without BH limitation, only one case was uncertain by CCMR, but was diagnosed as thrombus by FCMR (Fig. 4). No difference was found in another 29 patients. In other 24 patients with inconclusive CCMR results, de nitive diagnoses were made with the FCMR protocol in all patients, with positive diagnoses in 20 patients and negative diagnoses in 4 patients. Figures 5-6 show some cases were de nitively diagnosed by FCMR protocols.

Discussion
FCMR and CCMR protocols had comparable image quality ratings, left ventricular function assessment, and myocardial scar detection when both protocols were successfully obtained. The total acquisition time of FCMR including FB-CS-cine and FB-MOCO-LGE was signi cantly shorter than that of the CCMR including BH-cine and BH-LGE. This nding indicates that the FCMR protocol has feasibility in assessing cardiac function and myocardial viability. Furthermore, our results showed that the FCMR protocols could improve cardiac disease detection in patients with limited BH capabilities.
The CCMR imaging protocol requires multiple breath-holds to provide diagnostic image quality [14,15]. Generally, each BH takes 8-15 seconds per slice, with an additional pause that lasts 10 seconds before the next breath-hold session. Such repeated BH requirements can be challenging for patients who cannot hold their breath for extended periods. Also, to achieve su ciently high spatial and/or temporal resolutions during CCMR imaging, segmented k-space data are acquired over multiple heartbeats. Such segmented acquisition is prone to motion artifacts that could lead to repeated scans in case of suboptimal breath-holding. In our clinical setting, a few of the patients were unable to complete the CCMR examinations due to impaired BH capacity. The FCMR protocol not only removes the BH barrier which is particularly important for scanning most vulnerable patients with compromised BH capability, it also improves the scan e ciency. In addition, single-shot readout effectively eliminates breathing motion artifacts in both FB-CS-cine and FB-MOCO-LGE images [14][15][16]. High quality images were acquired for cine with CS acceleration, the high image quality of the CS technique translated into high agreement for LVF. Also, high quality images were acquired for LGE by combining non-rigid MOCO and averaging of multiple single-shot measurements.High agreement between the BH and FB MOCO technique was also achieved for LGE, with a non signi cant difference of LGE presence or types.
Our study found that there was no difference in LVF calculation and LGE detection between CCMR and FCMR images obtained from 30 patients without BH impairment, which was consistent with previous studies [3][4][5][7][8][9]. However, the study show that the IQ in FB CS cine is lower than BH cine. We observed that FB-CS-cine scans sometimes lead to a little of image blurring and low spatial resolution. There were some reasons as following [17]. First, FB-CS-cine was susceptibility for fold over artifacts, therefore, the eld of view must cover the entire anatomy, and thus, some penalty in spatial resolution may occur in relation to the patient's anatomy. Second, in some scans, ow-related artifacts occurred in the phaseencoding direction during systole because the sparsity in the temporal domain may be limited in anatomic regions of very high ow.
Overall, FCMR imaging leads to consistent images for diagnosis in all patients, regardless of whether they could hold their breath or not. In comparison, the IQ of CCMR depends on the BH capability of a patient during data acquisition. For patients with BH impairment, CCMR images suffer from severe motion artifacts, interfering the radiologist' ability to interpret morphologic cardiac structures, cardiac function calculations, and LGE detection. FCMR obtained consistently good quality images even in patients with compromised BH capabilities. It has been shown to be an effective alternative to CCMR in this study, expanding the application range of CMR imaging.

Limitations
There were several limitations to this study. First, the current study assessed FCMR and CCMR scans in patients with various cardiac diseases, complicating the comparison of the two protocols. Secondly, no advanced MRI sequences, such as mapping, perfusion, and ow quanti cation were performed in the study since they are not part of the standard CMR protocols at our institution. Thirdly, we have not yet assessed the incremental bene t of T2-weighted short-tau inversion recovery imaging to identify edema because there is no optimized free-breathing sequence available. Finally, the sample size is relatively small, only 24 patients with BH impairment need FCMR as a replacement for CCMR. The encouraging results from this study warrants future study with a larger sample size to demonstrate the clinical utility of free-breathing CMR.

Conclusions
We demonstrated that FCMR imaging could be used as an alternative technique in patients with BH impairment to obtain high-quality images. FCMR signi cantly shortens the time needed for CMR imaging and resulted in improved image quality. We believe that the FCMR protocol will allow the fast screen of cardiac diseases in clinical practice, with the potential to increase both the throughput and robustness of CMR.

Declarations
Funding None

Competing interests
The authors declare that they have no competing interests.

Code availability
Not applicable Authors' contributions KY Wang conceived the study, performed statistical analysis, and drafted the manuscript.XM Bi participated in design of the study, assisted in the interpretation of the results, and helped to revise the manuscript. Michaela Schmidt contributed to the sequence development, implementation on the scanner and helped to revise the manuscript. Jing An participated in the design of the study and coordination and helped to revise the manuscript. Jie Zheng helped to revise the manuscript. Jingliang Cheng assisted in the interpretation of the results and helped to revise the manuscript. Shuman Li and WenBo Zhang quantitatively measured cardiac function,and made the diagnosis respectively. All authors have read and approved the nal manuscript.
Ethics approval and consent to participate Approval was obtained from the local ethics committee. The number is 2019-LW-029. All subjects/ legal guardians gave written consent and assent as appropriate.

Consent for publication
The local ethics committee approved the use of images and content from this study. Consent and assent were signed for all subjects prior to publication.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Figure 2
These images show a randomly selected patient that did not have breath-holding (BH) impairment. The free-breathing cardiac magnetic resonance (FCMR) protocols were performed after the conventional cardiovascular magnetic resonance (CCMR) protocols. Both protocols showed excellent image quality that had a 5-point rating. The display of cine-CMR images in both protocols showed that the patient suffers from heart failure with an enlarged left ventricle. The corresponding BH-late gadolinium enhancement (LGE) and motion-corrected (MOCO)-LGE views showed normal in this patient.  Images of a patient with an uncertain diagnosis on conventional cardiovascular magnetic resonance (CCMR) imaging. A shadow was shown on the 4-chamber breath-holding (BH)-cine (a2) and BH-late gadolinium enhancement (BH-LGE) images (b2); however, it was uncertain that the lesion was an artifact, tumor, or thrombus. On free-breathing cardiac magnetic resonance (FCMR) imaging, an abnormal signal oscillated with the cardiac cycle at FB-CS-cine (a1), and no enhancement was found on motion-corrected (MOCO)-LGE images(b1,c). We, therefore, diagnosed a thrombus, which was con rmed on histopathology(d). Conventional cardiovascular magnetic resonance (CCMR) imaging was performed rst. Free-breathing CMR (FCMR) imaging was performed additionally due to poor image quality on the CCMR images.
Obvious artifacts were found on the CCMR imaging, and the image quality was poor. There were no artifacts on FCMR imaging, and the image quality had a 5-point rating. The corresponding breathing hold late gadolinium enhancement (LGE) images demonstrate non-diagnosis (artifact or non-ischemiac LGE).

Figure 6
Images show a few cases with various cardiac diseases acquired with breath-holding (BH)-LGE (top row) and corresponding motion-corrected (MOCO)-late gadolinium (LGE) (bottom row) acquired under freebreathing. Top row: Pictures (a1-d1) show non-diagnostic BH LGE imaging. Bottom row: corresponding FB-MOCO-LGEimages with the following diagnosis: (a2) Negative;(b2) An apical transmural myocardial infarction with a left anterior descending (LAD) distribution;(c2) Hyperenhancement at the junction of the interventricular septum and the right ventricular free wall;(d2) Hyperenhancement involve of the mitral valves and intramural septa.