We demonstrate that myocardial T1 values obtained in an investigator-led, single vendor, multicenter study based on similar imaging infrastructure and unified imaging parameters, can be reliably reproduced at the core lab as well as the participating sites by standardized image acquisition and post-processing approach. We provide reference values for native T1 and hybrid measures for 1.5 and 3 T magnetic field strengths in healthy human myocardium. The present study provides a proof of transferability of a T1 mapping methodology beyond a single (and expert) center and suggests a pathway towards a wider use of T1 mapping.
A substantial body of evidence suggests that T1 mapping is sufficiently accurate, reproducible and robust to enter into clinical translational pathway; T1-values were found abnormal in a variety of cardiomyopathies and permit discrimination between normal and abnormal myocardium. Thus far, a couple of studies reported on the associations with outcomes, albeit short-term, in a selected patient population and single centre set-ups [
22],[
23]. Difficulties for immediate clinical translation also relate to the ongoing technical evolution of T1 mapping sequences, scarcity of multicenter and prospective controlled studies as well as outcome evidence in subgroups and in large populations [
11],[
24]. This is the first study to provide reference values for myocardium healthy humans, including native T1 and ECV based on a unified T1 mapping methodology at both field strengths, in a multicenter setting. The average T1 values obtained at 1.5 T field strength are closest to the segmental values obtained by Messroghli et al. [
13],[
20],[
25] using MOLLI in its original form, 3(3)3(3)5, which was also used for the current data acquisition. Advances in MRI scanning equipment with improved coils and shimming, combined with a rigorous postprocessing approach with motion correction, as well as considerably greater sample size, may explain the lower spread of native T1 values observed in the present study. Subsequent generations of MOLLI sequence, which introduced several parameter modifications, most noticeably a lower flip angle of 35° (compared to 50° in the original sequence), showed similar average myocardial native T1 values in healthy volunteers (Messroghli: 939 ± 24 msec; Piechnik, 976 ± 46 msec) [
26],[
27], and were also implemented across other vendor platforms. A series of publications from a single centre (National Institutes of Health, NIH) revealed either similar values at 1.5 T (Gai et al. 986 ± 168 msec, FA = 50° [
28]; Liu et al.: native T1: 977 ± 42 msec, FA 35° [
12]) or higher native T1 values (Nacif et al. native T1: 1034 ± 56 msec, FA 35°) [
29], with considerably greater scatter. T1 relaxation times increase with higher field strength, which is also reflected in our findings: myocardial native T1 values at 3 T are approximately 100 msec longer in comparison to 1.5 T. This observation is concordant with previous studies, including by Piechnick et al. (average SAX 1169 ± 45 msec) [
27], and several publications from the NIH (Kawel et al. 1286 ± 59 msec [
30]; Lee et al. (1315 ± 39 msec) [
31], and more recently, Von Knobelsdorff-Brenkenhoff et al. (1159 ± ~73 msec) [
32]. The magnitude of native T1 values at 3 T observed in the present multicenter study concord with the values in patient cohort comparisons studies we have reported on previously [
14]-[
16], supporting the unchanging source of results based on a uniform imaging platform. We also provide further insights into the reference ranges for λ and ECV based on a MOLLI sequence at both field strengths based on the bolus technique [
19],[
22],[
30]. Our findings concord with previous reports concerning the average and spread of ECV values in healthy subjects (at 1.5 T: Liu et al. 0.27 ± 0.03 (calculated as an average of values for men: 0.26 ± 0.03 and women: 0.28 ± 0.03) [
12], Wong et al. ~0.24 ± 0.02 [
22]; at 3 T: Kawel et al. ~0.29 ± 0.03 (estimated from the Figure
2 at ~20 min time-point) [
30], Lee et al. 0.27 ± 0.10 [
31]), and the independency of the calculated parameters from the field strengths.
Sequence parameters, vendors’ specific set-up and standardized acquisition in part explain the observed diversity in T1 values in the above studies. A standardized approach to postprocessing is an additional important consideration for reproducibility and spread of T1 measurements, allowing robust discrimination between health and disease. We and others have previously shown that there are significant regional variations of native T1-values in SAX slices of normal subjects [
16],[
27],[
33]-[
35], with differences between the septal and lateral segments ranging between 60 to 150 msec. We have previously shown that native T1 measurement in the septum provide the most robust post-processing approach with an excellent intra-observer and inter-observer reproducibility irrespective of the field strength [
14]-[
16]. We now show that this post-processing approach is robust also in a multicenter setting, providing meaningful values on the expected reference ranges in healthy myocardium. Regional variation in segmental values may also account for a higher spread of values in some of the above studies, because T1 measurements in average SAX approach integrate native T1 values observed in all myocardial segments. It is unlikely that these regional differences represent a true difference in tissue composition.
We found no relationship between T1 values and age. Several previous publications showed decreasing native T1 values [
36] or increasing ECV values with age [
12],[
22]. Whereas decreasing trend with age is difficult to explain, the latter studies used a cross-sectional study design and investigated subclinical or overt disease, respectively. We have shown previously that T1 values increase with age in patients with cardiomyopathies [
15]. The discrepancy with previous results in healthy cohorts indicates that characterisation of healthy aging of the myocardium is challenging and complicating simple comparisons of age-related changes in T1 values. Previous studies also showed associations with gender, whereby age-dependency was stronger in men, and older females displaying higher native T1 or hybrid values [
12],[
36]. We found no gender differences in T1 values and a weak association for hybrid indices with males at 1.5 T; however, we could not reproduce such trend at 3 T. Of note, in a selected subgroup of subjects with very low cardiovascular risk, Liu et al. showed no ECV differences between women and men [
12], analogous to our findings. It is possible that age and gender differences in T1 values may relate to subclinical and clinical disease in cross-sectional studies, but may not be a profound feature in healthy aging. Lastly, whereas all sites used a single type of GBCA, gadobutrol, we reveal that non-uniformity of contrast agent doses leads to appreciable differences in hybrid indices at both field strengths. These findings were not expected, as it is generally considered that λ and ECV account for most of these sources of variation, which otherwise complicate cross-sites comparisons [
9],[
28].
Limitations
A few limitations apply to this study. It is recognized that the MOLLI variant used in our study affords a greater precision in terms of tissue characterisation (i.e. discrimination between health and disease) compared to the measurements derived from other MOLLI scheme variants (which are more accurate in terms of T1 value estimation) [
10],[
11], therefore, our ECV calculation is likely to be more precise. Ongoing advances and optimization of MOLLI schemes and pulse sequence parameters have shown that estimation of true T1 values can be obtained with greater accuracy [
10],[
11]. However whilst improved accuracy is attainable, high precision of T1 estimates supporting ability to discriminate between health and disease is fundamental, supporting diagnostic and prognostic role of a biomarker in clinical use. Both, precision and high discriminatory ability have been demonstrated for the approach chosen in the current study [
14]-[
16]. It may be argued that optimized FA (e.g. 35°) may be superior to our choice of 50° due to a higher SNR and less susceptibility to off-resonance effects [
25],[
37]. However, a higher FA also leads to stronger magnetisation transfer effects, which differ between normal and abnormal myocardium, adding to the discriminatory ability of the chosen method [
38]. Asymptomatic healthy subjects represent an ideal target population for derivation of normal ranges. In selecting healthy volunteers in our study, we strived to also account for exclusion of subclinical disease by a further inclusion criterion of normal findings on routine CMR [
17],[
39]. These same rigorous inclusion criteria were applied to the subgroup of normotensive low risk patients, primarily intended to compensate for the lower number of contrast studies in healthy volunteers. Because groups were similar for clinical characteristics and routine CMR findings (and subsequently T1 values), we believe that bias introduced by their inclusion in age-gender related comparisons is negligible. Hematocrit, which is used in ECV calculation has only been available in a minority of subjects and has not been sampled at the time of CMR studies [
9]. Thus, normal ranges for hybrid measures may bear inaccuracies. In the present study we controlled for, reported on or assessed many of the influences, which complicate T1 values comparisons, including CMR platform, technique, pulse sequence parameter selections, field strength, type of GBCA and post-processing of T1 measurement. While a single vendor platform might potentially be perceived as a limitation to a wider transferability of our results, the multicenter nature of our data overcomes several limitations by delivering evidence, which is fundamental and immediately useful to the centers using same hardware set-up. This adds to the future potential of providing T1 mapping as a commercial clinical application as the evidence continues to emerge. Evidence for robustness of clinical applications also enhances the chances for multivendor agreements, providing the clarity on a common minimum standard for clinical application of a T1 mapping sequence.