Comparison of T1 mapping techniques for ECV quantification. Histological validation and reproducibility of ShMOLLI versus multibreath-hold T1 quantification equilibrium contrast CMR
© Fontana et al.; licensee BioMed Central Ltd. 2012
Received: 26 June 2012
Accepted: 19 December 2012
Published: 28 December 2012
Myocardial extracellular volume (ECV) is elevated in fibrosis or infiltration and can be quantified by measuring the haematocrit with pre and post contrast T1 at sufficient contrast equilibrium. Equilibrium CMR (EQ-CMR), using a bolus-infusion protocol, has been shown to provide robust measurements of ECV using a multibreath-hold T1 pulse sequence. Newer, faster sequences for T1 mapping promise whole heart coverage and improved clinical utility, but have not been validated.
Multibreathhold T1 quantification with heart rate correction and single breath-hold T1 mapping using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) were used in equilibrium contrast CMR to generate ECV values and compared in 3 ways.
Firstly, both techniques were compared in a spectrum of disease with variable ECV expansion (n=100, 50 healthy volunteers, 12 patients with hypertrophic cardiomyopathy, 18 with severe aortic stenosis, 20 with amyloid). Secondly, both techniques were correlated to human histological collagen volume fraction (CVF%, n=18, severe aortic stenosis biopsies). Thirdly, an assessment of test:retest reproducibility of the 2 CMR techniques was performed 1 week apart in individuals with widely different ECVs (n=10 healthy volunteers, n=7 amyloid patients).
More patients were able to perform ShMOLLI than the multibreath-hold technique (6% unable to breath-hold). ECV calculated by multibreath-hold T1 and ShMOLLI showed strong correlation (r2=0.892), little bias (bias -2.2%, 95%CI -8.9% to 4.6%) and good agreement (ICC 0.922, range 0.802 to 0.961, p<0.0001). ECV correlated with histological CVF% by multibreath-hold ECV (r2= 0.589) but better by ShMOLLI ECV (r2= 0.685). Inter-study reproducibility demonstrated that ShMOLLI ECV trended towards greater reproducibility than the multibreath-hold ECV, although this did not reach statistical significance (95%CI -4.9% to 5.4% versus 95%CI -6.4% to 7.3% respectively, p=0.21).
ECV quantification by single breath-hold ShMOLLI T1 mapping can measure ECV by EQ-CMR across the spectrum of interstitial expansion. It is procedurally better tolerated, slightly more reproducible and better correlates with histology compared to the older multibreath-hold FLASH techniques.
The myocardial extracellular space is expanded by focal fibrosis , diffuse fibrosis [2–6] or infiltration, such as amyloidosis . It can be measured non-invasively by cardiovascular magnetic resonance (CMR) using pre and post contrast T1 relaxation times of blood and myocardium (the latter at sufficient contrast equilibrium) with correction for the blood volume of distribution via the haematocrit [1, 2, 8]. A number of T1 measurement techniques exist including multibreath-hold techniques such fast low angle single shot inversion recovery (“multibreath-hold FLASH-IR”). Here the sequence is performed at increasing inversion times to generate T1 recovery curves and heart rate correction [9, 10]. Newer, faster sequences such as MOLLI (Modified Look-Locker Inversion recovery)  perform IR measurements in a single breath-hold. A recent evolution of MOLLI, the Shortened-MOLLI (ShMOLLI)  improves clinical utility with a shorter breath-hold and immediate map reconstruction directly on the scanner. ECV measurements have been performed and validated using MOLLI for bolus-only protocols. Equilibrium contrast CMR (EQ-CMR) with single breath-hold sequences has not yet been validated for ECV assessment. ECV mapping with such sequences would be a significant technical advance, being easier for patients with shorter breath-holds (either shorter scans or whole heart coverage) and easier quantification.
We hypothesised that ECV mapping using ShMOLLI would be superior to the multibreath-hold FLASH-IR technique. This was assessed in three ways: firstly, to determine any bias in ECV between the two techniques. Secondly, we compared both CMR techniques with histological collagen volume fraction (CVF%). Finally, we assessed the reproducibility of both CMR techniques. For equivalence of contrast conditions between the two techniques, we used the primed infusion technique, equilibrium contrast CMR.
Patient studies: healthy normal subjects and disease groups
Normal subjects (n=50, median age 47±17, 53% male) were recruited through advertising within the hospital, university and general practitioner surgeries. All normal subjects had no history or symptoms of cardiovascular disease or diabetes. Four subjects had been prescribed statin therapy for hypercholesterolaemia (primary cardiovascular prevention), but no other normal subject was taking any cardiovascular medication. All subjects had a normal blood pressure, 12 lead electrocardiogram and clinical CMR scan.
Patients (n=50) were prospectively recruited from tertiary clinical and research departments at the Heart Hospital or the National Amyloidosis Centre, Royal Free Hospital:  12 patients with hypertrophic cardiomyopathy meeting the diagnostic criteria (average age 52±13, 60% male).  18 patients with severe aortic stenosis waiting for aortic valve replacement (median age: 71±10, 72% male).  20 patients with cardiac AL amyloidosis with disease proven by non-cardiac biopsy and cardiac involvement ascertained through echocardiography, supported by a Mayo clinic classification score of 2 or 3 (average age: 60±10, 75% male). Patients with atrial fibrillation or a contra-indication to contrast CMR examination were excluded from the study.
24 patients with severe aortic stenosis listed for surgical aortic valve replacement were studied. An intraoperative deep myocardial biopsy (Tru-Cut needle) was taken in aortic stenosis. Samples were stained and analysed for CVF%, as previously described . 6 patients were excluded from further analysis (2 patients had focal fibrosis detected as LGE in the basal septum; 2 patients had biopsies consisting solely of endocardial fibrosis; in 1 patient multibreath-hold T1 quantification was not performed because the patient was unable to breath-hold; 1 patient had a pulmonary oedema during the scan) leaving 18 patients.
For test:retest interstudy reproducibility, 10 normal subjects and 7 patients with amyloid underwent repeat scanning, one week apart. The analysis was carried out by a single observer blinded.
Data analysis and statistics
Results were analysed using SPSS (Chicago, IL, USA, version 19). ECV values were found to be normally distributed in each group (Kolmogorov-Smirnov test, p>0.05 for each data set) and so expressed as mean ± standard deviation. We used Intraclass Correlation Coefficient (ICC) and Bland-Altman plot to compare ECV values from the two methods. Interstudy reproducibility for the CMR measurement of ECV was assessed by calculating the ICC and Bland Altman plots. To compare the squared difference of paired ECV measurements Wilcoxon signed rank test was used. A p value <0.05 was considered statistically significant.
Mean ECV ± standard deviation assessed using multibreath-old T1 quantification and ShMOLLI T1 in normal subjects and disease groups
Multibreath-hold T1 ECV (%)
ShMOLLI ECV (%)
Normal subjects (n=50)
CMR ECV quantification requires accurate and rapid T1 relaxation time calculation. We have found that ECV quantification using ShMOLLI compared to multibreath-hold T1 quantification has a greater chance of technical success on all patients, less bias over a wide range of ECV measurements, a higher correlation with histological CVF% as well as better reproducibility. These four findings combine with key advantages of the mapping technique: a single breath-hold per T1 map, simple analysis and the potential for whole heart ECV quantification. Therefore, it is our opinion that T1 mapping technique ShMOLLI is the superior CMR technique for ECV quantification.
T1 mapping by means of the multi-breath-hold technique is one of the most commonly utilised methods for T1 quantification [9, 10]. The main advantage of this technique is that it is not vendor specific and it has been heavily optimised by everyday clinical practice to obtain high resolution LGE images. However it also has a number of limitations. Firstly, in order to map a single cardiac slice, it requires the sequence to be run up to 9 times at increasing inversion times. The average breath-hold time for each sequence is 14 seconds (longer at slower heart rates). If the patient cannot hold their breath for the duration of the sequence, artefact will appear on any one of the images. This may also occur if the patient has an arrhythmia. As each slice takes so many breath-holds to map, this method can not be used clinically for whole heart mapping (i.e. of multiple cardiac slices). Once the images have been obtained, the offline post processing is laborious and the results require heart rate correction for the calculated T1 relaxations times .
We have found that ECV quantification using ShMOLLI improves on several practical aspects compared to multibreath-hold T1 quantification. ShMOLLI imaging is characterised by lower breath-hold failure rate, less bias over a wide range of ECV, a slightly higher correlation with histological collagen volume fraction and slightly better reproducibility, although it does not reach statistical significance. Shorter acquisition times and direct T1 map calculation on the scanner  ensures ShMOLLI is quicker to perform and analyse with a potential to provide whole heart ECV quantification. While currently ShMOLLI is vendor specific, its predecessor MOLLI exists for more than one platform .
Future techniques for T1 measurement are likely to be based on mapping. Further advances may include higher resolution imaging with reduction of partial volume effects, with that incorporate motion correction and improved capabilities for measuring longer T1s [14–17]. We preferred here to re-iterate the T1 map for maximum accuracy – a step that will likely be un-necessary in future refinements. Preliminary exploration is being made of combining the two T1 maps into an ECV map using further non-rigid registration .
This study has limitations. We have not presented the phantom work comparing ShMOLLI and FLASH-IR T1 estimation as this was primarily an ECV clinically-orientated paper with many of the likely confounders present only in-vivo and not detectable by phantom work. Histology correlations were lower previously described . We believe this is primarily due to different population characteristics (the population examined here is older) and to a greater number of surgeons involved in the biopsy arm of this study (with associated reduced homogeneity of samples). Finally, FLASH-IR was compared to a single T1 mapping technique, ShMOLLI. MOLLI,its variants and other T1 mapping techniques such as SACHA  were not considered in this study.
As ECV quantification experience increases, it is likely that technology will advance to become more precise, accurate and automated. Our study represents the first such paper and demonstrates that single breath-hold ShMOLLI T1 mapping can quantify ECV by EQ-CMR across the spectrum of interstitial expansion, and that it is clinically more straightforward with improvements in reproducibility and histological correlation when compared to the older multibreath-hold FLASH techniques.
ECV quantification by single breath-hold ShMOLLI T1 mapping can measure ECV by EQCMR across the spectrum of interstitial expansion. It is procedurally better tolerated, slightly more reproducible and better correlates with histology compared to the older multibreathhold FLASH techniques.
This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. SN and SKP acknowledge support from the National Institute for Health Research Oxford Biomedical Research Centre Programme. JCM is funded by HEFCE. SKW, DMS, ASF are funded by the British Heart Foundation. SN also acknowledges support from the Oxford British Heart Foundation Centre of Research Excellence.
US patent pending 61/387,591: SKP. SYSTEMS AND METHODS FOR SHORTENED LOOK LOCKER INVERSION RECOVERY (Sh-MOLLI) CARDIAC GATED MAPPING OF T1. September 29, 2010. All rights sold exclusively to Siemens Medical. All the other authors declare that they have no competing interests.
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