Comparison of MOLLI, shMOLLLI, and SASHA in discrimination between health and disease and relationship with histologically derived collagen volume fraction

Comparison of MOLLI, shMOLLLI, and SASHA in discrimination between health and disease and... Abstract Aims To determine the bioequivalence of several T1 mapping sequences in myocardial characterization of diffuse myocardial fibrosis. Methods and results We performed an intra-individual sequence comparison of three types of T1 mapping sequences [MOdified Look-Locker Inversion recovery (MOLLI), Shortened MOdified Look-Locker Inversion recovery ((sh)MOLLI), and SAturation recovery single-SHot Acquisition (SASHA)]. We employed two model diseases of diffuse interstitial fibrosis [patients with non-ischaemic dilated cardiomyopathy (NIDCM), n = 32] and aortic stenosis [(AS), n = 25)]. Twenty-six healthy individuals served as controls. Relationship with collagen volume fraction (CVF) was assessed using endomyocardial biopsies (EMB) intraoperatively in 12 AS patients. T2 mapping (GraSE) was also performed. Myocardial native T1 with MOLLI and shMOLLI showed, firstly, an excellent discriminatory accuracy between health and disease [area under the curves (P-value): 0.94 (0.88–0.99); 0.87 (0.79–0.94); 0.61 (0.49–0.72)], secondly, relationship between histological CVF [native T1 MOLLI vs. shMOLLI vs. SASHA: r = 0.582 (P = 0.027), r = 0.524 (P = 0.046), r = 0.443 (P = 0.150)], and thirdly, with native T2 [r = 0.628(P < 0.001), r = 0.459 (P = 0.003), r = 0.211 (P = 0.083)]. The respective relationships for extracellular volume fraction with CVF [r = 0.489 (P = 0.044), r = 0.417 (0.071), r = 0.353 (P = 0.287)] were significant for MOLLI, but not other sequences. In AS patients, native T2 was significantly higher compared to controls, and associated with levels of C-reactive protein and troponin. Conclusion T1 mapping sequences differ in their bioequivalence for discrimination between health and disease as well as associations with diffuse myocardial fibrosis. T1 mapping , MOLLI , shMOLLI , SASHA , collagen Introduction Myocardial T1 mapping provides a novel concept in quantitative tissue characterization, yielding a value, unlike relying on visually recognizable contrast differences. Thus, T1 mapping measurements can be used to relay biologically important properties in a quantitative manner, including the presence and severity of abnormal myocardium in many cardiac conditions. T1 indices have a potential to improve clinical diagnosis and risk stratification, particularly in conditions with diffuse myocardial involvement.1 Despite the surge in evidence, the immediate clinical translation of these techniques is complicated by multiple variants of similar T1 mapping sequences. Each sequence and its modification yield different normal values and ranges, and show variable diagnostic performance in detection of abnormalities in human myocardium. Thus, each sequence will represent an individual diagnostic test, necessitating an individual clinical validation and standardization.2 T1 mapping sequences employed in myocardial characterization differ principally in magnetization preparation by either an inversion recovery (IR) or a saturation recovery (SR) prepulse (reviewed in Higgins et al.3) The many variants of these two approaches are further distinguished by different schemes of image acquisition (e.g. number of prepulses/images/pauses) and readout parameters [flip angle (FA), time delay, adiabatic prepulse, etc]. The sequence most commonly reported is based on the IR sequence MOdified Look-Locker (MOLLI). Following its original publication,4 numerous MOLLI variants have been developed either to achieve shorter breath-holds5,6 or greater T1 accuracy.7 SR sequences benefit from a much shorter period of T1 relaxation following a SR preparation8,9 and absence of history of magnetization of prior heartbeats, thus, shortening the overall acquisition time and improving the T1 accuracy, respectively. All T1 mapping methods are continuously and actively modified (‘optimized’) in terms of protocol parameters, scanner software versions, practical scanning methodology and methods of analysis, as well as manufacturer-specific implementations. In this study, we undertook sequence comparison of the 3 most commonly reported T1 mapping sequences—within the same individual—to examine their bioequivalence, or performance in vivo, in terms of diagnostic accuracy, relationships with histologically derived collagen volume fraction (CVF), and their T2 sensitivity by comparison with T2 mapping, in two model diseases of diffuse myocardial fibrosis; non-ischaemic dilative cardiomyopathy (NIDCM) and aortic stenosis (AS). Methods Consecutive patients from Guys and St. Thomas’ and Kings College Hospitals were invited to participate in this study: Patients with NIDCM10 (n = 32). Prior to their enrolment, the diagnosis was confirmed by cardiovascular magnetic resonance (CMR) on the basis of increased LV end-diastolic volume indexed to body surface area and reduced LV ejection fraction (EF < 50%) compared with published reference ranges normalized for age and sex.11 Several of these subjects were included in our previous publications.10,12,13 Patients with severe AS (n = 25) were identified from cardiology and cardiothoracic surgery outpatient clinics. AS was the leading valve problem based on Doppler echocardiographic demonstration of mean aortic valve pressure gradient >40 mmHg.14 Asymptomatic and normotensive subjects (n = 26), taking no regular medication and with no significant medical history and normal CMR findings, including volumes and mass, served as controls.12,15 Control subjects were recruited as a part of the parallel project into the normal values.16 The subgroup was selected to provide an age-gender matched control group to the AS group.Exclusion criteria for all subjects are detailed in supplementary material. Blood samples for haematocrit in AS patients were obtained contemporaneously at the time of the CMR procedure, whereas in patients with NIDCM these were based on the clinical blood tests.10 Analysis of serological cardiac biomarkers, including N-terminal-pro brain natriuretic peptide (NT-BNP), type 1 procollagen C-terminal propeptide (PICP), high-sensitive (hs-) troponin and hs-C-reactive protein (CRP), was performed using commercial platforms. The study protocol was reviewed and approved by the local ethics committee, and written informed consent was obtained from all participants. All procedures were carried out in accordance with the Declaration of Helsinki (2013). Image acquisition and analysis All sequence parameters are detailed in the Supplementary material. Subjects underwent a routine clinical protocol for cardiac volumes and mass (with cine imaging) and tissue characterization with T1 mapping and late gadolinium enhancement (LGE) imaging using 3-Tesla MRI scanner equipped with advanced cardiac package and multi-transmit technology (Achieva, Philips Healthcare, Best, The Netherlands).10,12,17 T1 mapping was performed using two MOLLI variants [the original MOLLI4,10,12 and Shortened MOdified Look-Locker Inversion recovery (shMOLLI)5] and a SR variant, SAturation recovery single-SHot Acquisition (SASHA).8 Sequences were acquired in random order (to avoid bias) in a single midventricular short axis (SAX) slice, prior to and 15 minutes after intravenous administration of gadobutrol (0.2 mmol/kg per body weight, Gadovist®, Bayer Healthcare, Leverkusen, Germany). T2 mapping was performed in the same geometry using a hybrid gradient and spin echo GraSE sequence. CMR analysis was performed using commercially available software (CVI42®, Circle Cardiovascular Imaging Ltd, Calgary, Canada) following standardized post-processing recommendations.10,18 LGE images were visually examined for the presence of regional scar tissue in two phase-encoding directions and confirmed as positive if the visually positive regions had a SI > 4 standard deviations (SD) from normal regions.17 Recovery rate of T1 and T2 relaxation for all sequences was measured conservatively within the septal myocardium, using PRIDE (Philips, Best, The Netherlands), as previously described and validated.12,15 Areas of LGE were excluded from the mapping regions of interests (ROI). Care was taken to avoid contamination of myocardial signal with the blood pool. In addition to T1-values of native and post-contrast myocardium the gadolinium extracellular partition coefficient, the haematocrit-corrected extracellular volume fraction (ECV) was calculated.19 Myocardial biopsies and histological analysis Several (n ≥ 3 per person) intraoperative deep endomyocardial biopsy (EMB) samples were obtained in 12 AS patients using either biopsy forceps (Novatome, Scholten®) or direct surgical excision, as per choice of operator. EMBs were sampled from the mid-portion of the interventricular septum, avoiding the basal fibrotic membranous part. Sample preparation and analysis approach are described in supplementary material. Mean percent fibrosis (CVF), fibrosis heterogeneity (SD between fields), patient heterogeneity (interquartile range, IQR), and inter-observer coefficient of variation (CoV) are reported. Statistical analysis Statistical analysis was performed using SPSS software (SPSS Inc., Chicago, IL, USA, version 23.0). Normality of distributions was tested using Wilks-Shapiro statistic. Categorical data are expressed as percentages, and continuous variables as mean ± SD or median (interquartile range), as appropriate. Comparisons of the means between groups were performed using one way ANOVA (with Bonferroni posthoc tests for the differences from controls). Associations between variables were detected by bivariate linear regression analyses. Repeatability of measurements were assessed using intraclass-correlations (ICC). Receiver operating characteristic (ROC) curves was used in discrimination between health and disease. All values are reported as mean±SD and a P-value of less than 0.05 was considered statistically significant. Results A total of 83 subjects completed the imaging protocol with the 3 T1 mapping sequences. Subject characteristics and CMR results are presented in Supplementary data online, Table S1. Groups were similar for age, gender, heart rate and diastolic blood pressure, whereas the body-mass index and systolic BP were significantly higher in AS patients. Compared to controls, both patient groups had significantly higher indexed left ventricular (LV) volumes, LV mass, left atrial size, and lower LV and RV ejection fraction (P < 0.05 for all). All patients with AS has increased LV wall thickness ≥12 mm, measured in diastole. Non-ischaemic LGE was present in a total of 10 NIDCM (31%) and 5 AS (20%) patients. Patients had significantly higher mean E/e′ on transthoracic echocardiography, as well as the levels of serological cardiac biomarkers. Native T1 and ECV data show progressively larger imprecision and variation in normal controls from MOLLI to ShMOLLI to SASHA (see Supplementary data online, Table S2).9,20 Compared with controls, native T1 and ECV were significantly higher in both patient groups for MOLLI and shMOLLI sequences (P < 0.01), whereas SASHA only revealed a significant difference between controls and patients with NIDCM. Post-contrast T1 values were significantly different for the MOLLI sequence but not shMOLLI or SASHA (Table 2). Native T2 was raised in NIDCM and AS patients, significantly in the latter group. Table 2 Summary of studies reporting on association between CVF and T1 mapping indices modified and adapted from1 (with permission) Collagen volume fraction%  Sequence  Pearson r (Sig)  No. of patients (cardiac disease)  GCAs (dose and type)  T1 Index  Histological staining  Aortic stenosis               Flett et al.21  GRE-IR  0.94 (0.001)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red   Bull et al.22  shMOLLI  0.655 (0.002)  19    Native T1  Picrosirius red   Fontana et al.23  GRE-IR  0.78 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red    shMOLLI  0.83 (<0.01)     White et al.24  shMOLLI  0.83 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (bolus)  Picrosirius red  0.84 (<0.01)  ECV (EQ)   de Meester de Ravenstein et al.25  MOLLI 3(3)3(3)5 (FA35°)  −0.15 (0.64)  12  (0.2 mmol/kg gadobutrol)  Native T1  Picrosirius red  −0.64 (0.024)    Post-contrast T1  0.91 (0.001)    ECV   Lee et al.26  MOLLI 3(3)3(3)5(FA35°)  0.77 (<0.01)  10    Native T1  Picrosirius red  Child  MOLLI 3(2)3(2)5(FA50°)  0.582 (0.027)  12  (0.2 mmol/kg gadobutrol)  Native T1  Masson-trichrome  −0.47 (0.065)  Post-contrast T1  0.498 (0.044)  ECV  shMOLLI  0.524 (0.046)  Native T1  −0.45 (0.140)  Post-contrast T1  0.417 (0.071)  ECV  SASHA  0.442 (0.150)  Native T1  −0.27 (0.411)  Post-contrast T1  0.353 (0.287)  ECV  Heart failure               Iles et al.27  VAST  −0.7 (0.03)  9 (IHD)  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Picrosirius red   Sibley et al.28  Look-Locker  −0.57 (<0.001)  47 (NICMs)  (0.2 mmol/kg gadodiamide)  Post-contrast T1  Masson trichrome   Mascherbauer et al.29  GRE-IR  −0.98 (<0.01)  9 (HFpPEF)  (0.2 mmol/kg gadobutrol)  Post-contrast T1  Masson Trichrome/Congo-red   Miller et al.30  MOLLI 3(3)3(3)5(FA 35°)  0.199 (0.437)  6 (IHD)  (0.2 mmol/kg (gadopentetate dimeglumine)  Native T1  Picrosirius red    −0.21 (0.69)  Post-contrast T1    0.945 (0.004)  ECV (bolus)   Aus dem Siepen et al.31  MOLLI 3(3)3(3)5(FA 35°)  0.85 (0.01)  45 (DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  ECV (bolus)  Acid Fuchsin Orange-G   Iles et al.32  VAST  0.73 (<0.001)  4 (1 IHD, 3 DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  LGE  Masson Trichrome    −0.64 (0.002)  Post-contrast T1   Kammerlander et al.33  MOLLI 5(3)3 (FA 35°) for native acquisition  0.493 (<0.002)  36 (mixed group)  (0.1 mmol/kg of gadobutrol)  ECV (bolus)  Tissue FAXS  MOLLI 4(1)3(1)2(FA 35°) for post-contrast acquisition  Hypertrophic cardiomyopathy               Flett et al.21  GRE-IR  R2 = 0.62(0.08), Tau = 0.52  8  (0.2 mmol/kg gadoterate meglumine)  ECV  Picrosirius red   Iles et al.32  VAST  −0.71 (0.01)  8  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Masson-trichrome  Collagen volume fraction%  Sequence  Pearson r (Sig)  No. of patients (cardiac disease)  GCAs (dose and type)  T1 Index  Histological staining  Aortic stenosis               Flett et al.21  GRE-IR  0.94 (0.001)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red   Bull et al.22  shMOLLI  0.655 (0.002)  19    Native T1  Picrosirius red   Fontana et al.23  GRE-IR  0.78 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red    shMOLLI  0.83 (<0.01)     White et al.24  shMOLLI  0.83 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (bolus)  Picrosirius red  0.84 (<0.01)  ECV (EQ)   de Meester de Ravenstein et al.25  MOLLI 3(3)3(3)5 (FA35°)  −0.15 (0.64)  12  (0.2 mmol/kg gadobutrol)  Native T1  Picrosirius red  −0.64 (0.024)    Post-contrast T1  0.91 (0.001)    ECV   Lee et al.26  MOLLI 3(3)3(3)5(FA35°)  0.77 (<0.01)  10    Native T1  Picrosirius red  Child  MOLLI 3(2)3(2)5(FA50°)  0.582 (0.027)  12  (0.2 mmol/kg gadobutrol)  Native T1  Masson-trichrome  −0.47 (0.065)  Post-contrast T1  0.498 (0.044)  ECV  shMOLLI  0.524 (0.046)  Native T1  −0.45 (0.140)  Post-contrast T1  0.417 (0.071)  ECV  SASHA  0.442 (0.150)  Native T1  −0.27 (0.411)  Post-contrast T1  0.353 (0.287)  ECV  Heart failure               Iles et al.27  VAST  −0.7 (0.03)  9 (IHD)  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Picrosirius red   Sibley et al.28  Look-Locker  −0.57 (<0.001)  47 (NICMs)  (0.2 mmol/kg gadodiamide)  Post-contrast T1  Masson trichrome   Mascherbauer et al.29  GRE-IR  −0.98 (<0.01)  9 (HFpPEF)  (0.2 mmol/kg gadobutrol)  Post-contrast T1  Masson Trichrome/Congo-red   Miller et al.30  MOLLI 3(3)3(3)5(FA 35°)  0.199 (0.437)  6 (IHD)  (0.2 mmol/kg (gadopentetate dimeglumine)  Native T1  Picrosirius red    −0.21 (0.69)  Post-contrast T1    0.945 (0.004)  ECV (bolus)   Aus dem Siepen et al.31  MOLLI 3(3)3(3)5(FA 35°)  0.85 (0.01)  45 (DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  ECV (bolus)  Acid Fuchsin Orange-G   Iles et al.32  VAST  0.73 (<0.001)  4 (1 IHD, 3 DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  LGE  Masson Trichrome    −0.64 (0.002)  Post-contrast T1   Kammerlander et al.33  MOLLI 5(3)3 (FA 35°) for native acquisition  0.493 (<0.002)  36 (mixed group)  (0.1 mmol/kg of gadobutrol)  ECV (bolus)  Tissue FAXS  MOLLI 4(1)3(1)2(FA 35°) for post-contrast acquisition  Hypertrophic cardiomyopathy               Flett et al.21  GRE-IR  R2 = 0.62(0.08), Tau = 0.52  8  (0.2 mmol/kg gadoterate meglumine)  ECV  Picrosirius red   Iles et al.32  VAST  −0.71 (0.01)  8  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Masson-trichrome  Types of sequences and a staining method used, as well as numbers of patients included, is also reported. GCAs, gadolinium contrast agents, IHD, ischaemic heart disease; HFpEF, heart failure with preserved ejection fraction; NICM, non-ischaemic cardiomyopathy; GRE-IR, gradient echo-inversion recovery; VAST, variable sampling of k-space in time. Table 2 Summary of studies reporting on association between CVF and T1 mapping indices modified and adapted from1 (with permission) Collagen volume fraction%  Sequence  Pearson r (Sig)  No. of patients (cardiac disease)  GCAs (dose and type)  T1 Index  Histological staining  Aortic stenosis               Flett et al.21  GRE-IR  0.94 (0.001)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red   Bull et al.22  shMOLLI  0.655 (0.002)  19    Native T1  Picrosirius red   Fontana et al.23  GRE-IR  0.78 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red    shMOLLI  0.83 (<0.01)     White et al.24  shMOLLI  0.83 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (bolus)  Picrosirius red  0.84 (<0.01)  ECV (EQ)   de Meester de Ravenstein et al.25  MOLLI 3(3)3(3)5 (FA35°)  −0.15 (0.64)  12  (0.2 mmol/kg gadobutrol)  Native T1  Picrosirius red  −0.64 (0.024)    Post-contrast T1  0.91 (0.001)    ECV   Lee et al.26  MOLLI 3(3)3(3)5(FA35°)  0.77 (<0.01)  10    Native T1  Picrosirius red  Child  MOLLI 3(2)3(2)5(FA50°)  0.582 (0.027)  12  (0.2 mmol/kg gadobutrol)  Native T1  Masson-trichrome  −0.47 (0.065)  Post-contrast T1  0.498 (0.044)  ECV  shMOLLI  0.524 (0.046)  Native T1  −0.45 (0.140)  Post-contrast T1  0.417 (0.071)  ECV  SASHA  0.442 (0.150)  Native T1  −0.27 (0.411)  Post-contrast T1  0.353 (0.287)  ECV  Heart failure               Iles et al.27  VAST  −0.7 (0.03)  9 (IHD)  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Picrosirius red   Sibley et al.28  Look-Locker  −0.57 (<0.001)  47 (NICMs)  (0.2 mmol/kg gadodiamide)  Post-contrast T1  Masson trichrome   Mascherbauer et al.29  GRE-IR  −0.98 (<0.01)  9 (HFpPEF)  (0.2 mmol/kg gadobutrol)  Post-contrast T1  Masson Trichrome/Congo-red   Miller et al.30  MOLLI 3(3)3(3)5(FA 35°)  0.199 (0.437)  6 (IHD)  (0.2 mmol/kg (gadopentetate dimeglumine)  Native T1  Picrosirius red    −0.21 (0.69)  Post-contrast T1    0.945 (0.004)  ECV (bolus)   Aus dem Siepen et al.31  MOLLI 3(3)3(3)5(FA 35°)  0.85 (0.01)  45 (DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  ECV (bolus)  Acid Fuchsin Orange-G   Iles et al.32  VAST  0.73 (<0.001)  4 (1 IHD, 3 DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  LGE  Masson Trichrome    −0.64 (0.002)  Post-contrast T1   Kammerlander et al.33  MOLLI 5(3)3 (FA 35°) for native acquisition  0.493 (<0.002)  36 (mixed group)  (0.1 mmol/kg of gadobutrol)  ECV (bolus)  Tissue FAXS  MOLLI 4(1)3(1)2(FA 35°) for post-contrast acquisition  Hypertrophic cardiomyopathy               Flett et al.21  GRE-IR  R2 = 0.62(0.08), Tau = 0.52  8  (0.2 mmol/kg gadoterate meglumine)  ECV  Picrosirius red   Iles et al.32  VAST  −0.71 (0.01)  8  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Masson-trichrome  Collagen volume fraction%  Sequence  Pearson r (Sig)  No. of patients (cardiac disease)  GCAs (dose and type)  T1 Index  Histological staining  Aortic stenosis               Flett et al.21  GRE-IR  0.94 (0.001)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red   Bull et al.22  shMOLLI  0.655 (0.002)  19    Native T1  Picrosirius red   Fontana et al.23  GRE-IR  0.78 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red    shMOLLI  0.83 (<0.01)     White et al.24  shMOLLI  0.83 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (bolus)  Picrosirius red  0.84 (<0.01)  ECV (EQ)   de Meester de Ravenstein et al.25  MOLLI 3(3)3(3)5 (FA35°)  −0.15 (0.64)  12  (0.2 mmol/kg gadobutrol)  Native T1  Picrosirius red  −0.64 (0.024)    Post-contrast T1  0.91 (0.001)    ECV   Lee et al.26  MOLLI 3(3)3(3)5(FA35°)  0.77 (<0.01)  10    Native T1  Picrosirius red  Child  MOLLI 3(2)3(2)5(FA50°)  0.582 (0.027)  12  (0.2 mmol/kg gadobutrol)  Native T1  Masson-trichrome  −0.47 (0.065)  Post-contrast T1  0.498 (0.044)  ECV  shMOLLI  0.524 (0.046)  Native T1  −0.45 (0.140)  Post-contrast T1  0.417 (0.071)  ECV  SASHA  0.442 (0.150)  Native T1  −0.27 (0.411)  Post-contrast T1  0.353 (0.287)  ECV  Heart failure               Iles et al.27  VAST  −0.7 (0.03)  9 (IHD)  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Picrosirius red   Sibley et al.28  Look-Locker  −0.57 (<0.001)  47 (NICMs)  (0.2 mmol/kg gadodiamide)  Post-contrast T1  Masson trichrome   Mascherbauer et al.29  GRE-IR  −0.98 (<0.01)  9 (HFpPEF)  (0.2 mmol/kg gadobutrol)  Post-contrast T1  Masson Trichrome/Congo-red   Miller et al.30  MOLLI 3(3)3(3)5(FA 35°)  0.199 (0.437)  6 (IHD)  (0.2 mmol/kg (gadopentetate dimeglumine)  Native T1  Picrosirius red    −0.21 (0.69)  Post-contrast T1    0.945 (0.004)  ECV (bolus)   Aus dem Siepen et al.31  MOLLI 3(3)3(3)5(FA 35°)  0.85 (0.01)  45 (DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  ECV (bolus)  Acid Fuchsin Orange-G   Iles et al.32  VAST  0.73 (<0.001)  4 (1 IHD, 3 DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  LGE  Masson Trichrome    −0.64 (0.002)  Post-contrast T1   Kammerlander et al.33  MOLLI 5(3)3 (FA 35°) for native acquisition  0.493 (<0.002)  36 (mixed group)  (0.1 mmol/kg of gadobutrol)  ECV (bolus)  Tissue FAXS  MOLLI 4(1)3(1)2(FA 35°) for post-contrast acquisition  Hypertrophic cardiomyopathy               Flett et al.21  GRE-IR  R2 = 0.62(0.08), Tau = 0.52  8  (0.2 mmol/kg gadoterate meglumine)  ECV  Picrosirius red   Iles et al.32  VAST  −0.71 (0.01)  8  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Masson-trichrome  Types of sequences and a staining method used, as well as numbers of patients included, is also reported. GCAs, gadolinium contrast agents, IHD, ischaemic heart disease; HFpEF, heart failure with preserved ejection fraction; NICM, non-ischaemic cardiomyopathy; GRE-IR, gradient echo-inversion recovery; VAST, variable sampling of k-space in time. ROC curves in discrimination between health and disease (all patients) are presented in Figure 1, with respective area under the curves [(AUCs), 95% confidence interval (95% CI)] for all T1 mapping indices and sequences listed in Table 1. Native T1 for MOLLI showed the greatest ability to discriminate between health and disease [AUC: 0.94 (0.88–0.99), P < 0.001; comparisons of AUCs: MOLLI vs. shMOLLI, SASHA and T2: P = 0.064, P < 0.001, P = 0.01, respectively]. Native T2 also showed a strong ability to differentiate between health and disease [AUC: 0.81 (0.73–0.89), P < 0.001]. Native T1 by MOLLI was an independent discriminator between health and disease (χ2 = 52, P < 0.001). Table 1 Discrimination between health and disease   Native T1    Post-contrast T1    ECV    Controls vs. all patients  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  MOLLI  0.94 (0.88–0.99)  <0.001  0.66 (0.54–0.77)  0.005  0.73 (0.64–0.83)  <0.001  ShMOLLI  0.87 (0.79–0.94)  <0.001  0.64 (0.52–0.75)  0.02  0.67 (0.58–0.79)  <0.001  SASHA  0.61 (0.49–0.72)  0.067  0.62 (0.50–0.73)  0.04  0.59 (0.46–0.72)  0.02  Native T2  0.81 (0.73–0.89)  <0.001  /  /  /  /    Native T1    Post-contrast T1    ECV    Controls vs. all patients  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  MOLLI  0.94 (0.88–0.99)  <0.001  0.66 (0.54–0.77)  0.005  0.73 (0.64–0.83)  <0.001  ShMOLLI  0.87 (0.79–0.94)  <0.001  0.64 (0.52–0.75)  0.02  0.67 (0.58–0.79)  <0.001  SASHA  0.61 (0.49–0.72)  0.067  0.62 (0.50–0.73)  0.04  0.59 (0.46–0.72)  0.02  Native T2  0.81 (0.73–0.89)  <0.001  /  /  /  /  The comparative performance of each sequence to discriminate between health and disease controls and all patients) for native T1, post-contrast T1 and ECV, using ROC-curve analysis to derive AUC. Table 1 Discrimination between health and disease   Native T1    Post-contrast T1    ECV    Controls vs. all patients  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  MOLLI  0.94 (0.88–0.99)  <0.001  0.66 (0.54–0.77)  0.005  0.73 (0.64–0.83)  <0.001  ShMOLLI  0.87 (0.79–0.94)  <0.001  0.64 (0.52–0.75)  0.02  0.67 (0.58–0.79)  <0.001  SASHA  0.61 (0.49–0.72)  0.067  0.62 (0.50–0.73)  0.04  0.59 (0.46–0.72)  0.02  Native T2  0.81 (0.73–0.89)  <0.001  /  /  /  /    Native T1    Post-contrast T1    ECV    Controls vs. all patients  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  MOLLI  0.94 (0.88–0.99)  <0.001  0.66 (0.54–0.77)  0.005  0.73 (0.64–0.83)  <0.001  ShMOLLI  0.87 (0.79–0.94)  <0.001  0.64 (0.52–0.75)  0.02  0.67 (0.58–0.79)  <0.001  SASHA  0.61 (0.49–0.72)  0.067  0.62 (0.50–0.73)  0.04  0.59 (0.46–0.72)  0.02  Native T2  0.81 (0.73–0.89)  <0.001  /  /  /  /  The comparative performance of each sequence to discriminate between health and disease controls and all patients) for native T1, post-contrast T1 and ECV, using ROC-curve analysis to derive AUC. Figures 1 View largeDownload slide Native T1 (A), post-contrast T1 (B), and ECV (C) in discrimination between health and disease for three sequences in all patients against healthy controls using ROC curve analysis. Figures 1 View largeDownload slide Native T1 (A), post-contrast T1 (B), and ECV (C) in discrimination between health and disease for three sequences in all patients against healthy controls using ROC curve analysis. Results of myocardial histology and associations with T1 mapping indices are presented in Table 2 (Figures 2 and 3). Procedurally, all EMBs were uneventful (n = 12). The mean histological CVF was 25.6% (intersubject IQR 10.1–43.2%, SD 18.6). There was an excellent agreement between the two observers (r = 0.95, P < 0.01; MD ± SD = 5.9 ± 4.6). Correlations between CVF with all T1 mapping indices for various sequences are included in Table 2 (Figure 4). There was moderate significant association for native T1 with MOLLI and shMOLLI, whereas correlation with SASHA was not significant. For ECV only MOLLI showed a significant association. Native T2 showed a mild but not significant association with CVF (r = 0.271, P = 0.24). Table 3 summarizes the correlations with serological markers for all T1 mapping indices in AS and NIDCM patients. Native T1 with MOLLI and shMOLLI, post-contrast T1 with MOLLI, and native T2 showed significant associations with N-terminal prohormone of brain natriuretic peptide (NT-proBNP), hs-troponin and CRP, but not PICP. Repeatability of measurements (ICCs) are reported in Supplementary Material. Table 3 Correlations between T1 and T2 mapping indices and serological markers in AS patients (n = 25) using Pearson correlation (r-statistic)   AS patients (n = 25)   NIDCM patients (n = 34)     T2 mapping (ms)  NT-proBNP  hs-Troponin  hs-CRP  PICP  NT-proBNP  hs-Troponin  hs-CRP  PICP  MOLLI                     Native T1 (ms)  0.628**  0.404*  0.324*  0.550**  0.284  0.441*  0.145  0.362*  0.316   Post-contrast T1 (ms)  −0.22  −0.470*  −0.334  −0.351*  −0.091  −0.328  −0.122  −0.291  −0.172   ECV (%)  0.248*  0.327  0.272  0.216  0.070  0.315  0.171  0.226  0.231  ShMOLLI                     Native T1 (ms)  0.459**  0.379*  0.217  0.409*  0.32  0.427*  0.160  0.350*  0.293   Post-contrast T1 (ms)  −0.16  −0.311  −0.201  −0.308  −0.19  −0.247  −0.114  −0.314  −0.189   ECV (%)  0.236*  0.234  0.195  0.142  0.068  0.285  0.125  0.164  0.193  SASHA                     Native T1 (ms)  0.211  0.095  0.099  0.213  0.083  0.136  0.083  0.291  0.233   Post-contrast T1 (ms)  0.027  −0.055  −0.025  −0.139  −0.069  −0.049  −0.053  −0.129  −0.061   ECV (%)  0.471  0.032  0.112  0.217  0.134  0.047  0.193  0.116  0.053  Native T2    0.414*  0.366*  0.382*  0.118  0.362*  0.162  0.351*  0.148    AS patients (n = 25)   NIDCM patients (n = 34)     T2 mapping (ms)  NT-proBNP  hs-Troponin  hs-CRP  PICP  NT-proBNP  hs-Troponin  hs-CRP  PICP  MOLLI                     Native T1 (ms)  0.628**  0.404*  0.324*  0.550**  0.284  0.441*  0.145  0.362*  0.316   Post-contrast T1 (ms)  −0.22  −0.470*  −0.334  −0.351*  −0.091  −0.328  −0.122  −0.291  −0.172   ECV (%)  0.248*  0.327  0.272  0.216  0.070  0.315  0.171  0.226  0.231  ShMOLLI                     Native T1 (ms)  0.459**  0.379*  0.217  0.409*  0.32  0.427*  0.160  0.350*  0.293   Post-contrast T1 (ms)  −0.16  −0.311  −0.201  −0.308  −0.19  −0.247  −0.114  −0.314  −0.189   ECV (%)  0.236*  0.234  0.195  0.142  0.068  0.285  0.125  0.164  0.193  SASHA                     Native T1 (ms)  0.211  0.095  0.099  0.213  0.083  0.136  0.083  0.291  0.233   Post-contrast T1 (ms)  0.027  −0.055  −0.025  −0.139  −0.069  −0.049  −0.053  −0.129  −0.061   ECV (%)  0.471  0.032  0.112  0.217  0.134  0.047  0.193  0.116  0.053  Native T2    0.414*  0.366*  0.382*  0.118  0.362*  0.162  0.351*  0.148  P-value of < 0.05 was statistically significant; * P < 0.05 ** P < 0.01. Table 3 Correlations between T1 and T2 mapping indices and serological markers in AS patients (n = 25) using Pearson correlation (r-statistic)   AS patients (n = 25)   NIDCM patients (n = 34)     T2 mapping (ms)  NT-proBNP  hs-Troponin  hs-CRP  PICP  NT-proBNP  hs-Troponin  hs-CRP  PICP  MOLLI                     Native T1 (ms)  0.628**  0.404*  0.324*  0.550**  0.284  0.441*  0.145  0.362*  0.316   Post-contrast T1 (ms)  −0.22  −0.470*  −0.334  −0.351*  −0.091  −0.328  −0.122  −0.291  −0.172   ECV (%)  0.248*  0.327  0.272  0.216  0.070  0.315  0.171  0.226  0.231  ShMOLLI                     Native T1 (ms)  0.459**  0.379*  0.217  0.409*  0.32  0.427*  0.160  0.350*  0.293   Post-contrast T1 (ms)  −0.16  −0.311  −0.201  −0.308  −0.19  −0.247  −0.114  −0.314  −0.189   ECV (%)  0.236*  0.234  0.195  0.142  0.068  0.285  0.125  0.164  0.193  SASHA                     Native T1 (ms)  0.211  0.095  0.099  0.213  0.083  0.136  0.083  0.291  0.233   Post-contrast T1 (ms)  0.027  −0.055  −0.025  −0.139  −0.069  −0.049  −0.053  −0.129  −0.061   ECV (%)  0.471  0.032  0.112  0.217  0.134  0.047  0.193  0.116  0.053  Native T2    0.414*  0.366*  0.382*  0.118  0.362*  0.162  0.351*  0.148    AS patients (n = 25)   NIDCM patients (n = 34)     T2 mapping (ms)  NT-proBNP  hs-Troponin  hs-CRP  PICP  NT-proBNP  hs-Troponin  hs-CRP  PICP  MOLLI                     Native T1 (ms)  0.628**  0.404*  0.324*  0.550**  0.284  0.441*  0.145  0.362*  0.316   Post-contrast T1 (ms)  −0.22  −0.470*  −0.334  −0.351*  −0.091  −0.328  −0.122  −0.291  −0.172   ECV (%)  0.248*  0.327  0.272  0.216  0.070  0.315  0.171  0.226  0.231  ShMOLLI                     Native T1 (ms)  0.459**  0.379*  0.217  0.409*  0.32  0.427*  0.160  0.350*  0.293   Post-contrast T1 (ms)  −0.16  −0.311  −0.201  −0.308  −0.19  −0.247  −0.114  −0.314  −0.189   ECV (%)  0.236*  0.234  0.195  0.142  0.068  0.285  0.125  0.164  0.193  SASHA                     Native T1 (ms)  0.211  0.095  0.099  0.213  0.083  0.136  0.083  0.291  0.233   Post-contrast T1 (ms)  0.027  −0.055  −0.025  −0.139  −0.069  −0.049  −0.053  −0.129  −0.061   ECV (%)  0.471  0.032  0.112  0.217  0.134  0.047  0.193  0.116  0.053  Native T2    0.414*  0.366*  0.382*  0.118  0.362*  0.162  0.351*  0.148  P-value of < 0.05 was statistically significant; * P < 0.05 ** P < 0.01. Figures 2 View largeDownload slide Representative images of patients with AS—Case 1. (A) Histological analysis with Mason Trichrome reveals mild-moderate interstitial fibrosis (CVF = 16%). MOLLI measurement reveal native T1 1068 ms (B) and ECV = 26%. Cine imaging in mid-systole: 3-chamber (C), LVOT (D) view and AV valve view, revealing significantly reduced AV opening (AV area by planimetry 0.56 cm2). There is no evidence of late gadolinium enhancement (F). NTproBNP 634 ng/L. Figures 2 View largeDownload slide Representative images of patients with AS—Case 1. (A) Histological analysis with Mason Trichrome reveals mild-moderate interstitial fibrosis (CVF = 16%). MOLLI measurement reveal native T1 1068 ms (B) and ECV = 26%. Cine imaging in mid-systole: 3-chamber (C), LVOT (D) view and AV valve view, revealing significantly reduced AV opening (AV area by planimetry 0.56 cm2). There is no evidence of late gadolinium enhancement (F). NTproBNP 634 ng/L. Figures 3 View largeDownload slide Representative images of patients with AS—Case 2. (A) Histological analysis with Mason Trichrome reveals considerable myocardial fibrosis (CVF 37%). MOLLI measurement in mid-ventricular SAX slice show native T1 1130 ms (B) and ECV 32%. Cine imaging in mid-systole: 3-chamber (C), LVOT (D) view and AV valve view, reduced AV opening (AV area by planimetry 0.37 cm2). Evidence of non-ischaemic late gadolinium enhancement in basal anteroseptal and inferolateral segments—red arrows (green arrow points to the basal RV structures, including RV outflow tract and pulmonary valve) (F). NTproBNP 1381 ng/L. Figures 3 View largeDownload slide Representative images of patients with AS—Case 2. (A) Histological analysis with Mason Trichrome reveals considerable myocardial fibrosis (CVF 37%). MOLLI measurement in mid-ventricular SAX slice show native T1 1130 ms (B) and ECV 32%. Cine imaging in mid-systole: 3-chamber (C), LVOT (D) view and AV valve view, reduced AV opening (AV area by planimetry 0.37 cm2). Evidence of non-ischaemic late gadolinium enhancement in basal anteroseptal and inferolateral segments—red arrows (green arrow points to the basal RV structures, including RV outflow tract and pulmonary valve) (F). NTproBNP 1381 ng/L. Figure 4 View largeDownload slide Correlations between T1 mapping measurements and histologically derived CVF—native T1 (A–C) and ECV (D–F). Figure 4 View largeDownload slide Correlations between T1 mapping measurements and histologically derived CVF—native T1 (A–C) and ECV (D–F). Discussion We demonstrate that T1 mapping sequences differ considerably in their performance in myocardial tissue characterization, as evidenced by differential ability to discriminate between health and disease and by diverse associations with myocardial CVF and T2 mapping. More specifically, our findings reveal that native T1 using MOLLI sequences show an excellent diagnostic performance in detecting the differences in myocardium between controls and patients. Myocardial T1 mapping with MOLLI sequences showed the strongest relationship with histologically derived CVF and with T2 mapping. A number of previous studies reported on associations with tissue collagen content or discrimination between health and disease (summarized in Figure 4, modified from1) We expand these findings by comprehensive and standardized intraindividual acquisition of more than one sequence and analysis of all T1 indices. Compared with a previous reports we found similar associations for native T1 with CVF for shMOLLI.22 For MOLLI, previous studies reported diverse associations for native T1 and CVF ranging between 0.15 and 0.77,1 and our results add to the favourable side of that range. Associations for ECV, however, were much lower for both shMOLLI23,24 and MOLLI.34 Several possible reasons may explain these findings, especially the type of sequences, given the implementation and optimization of shMOLLI and SASHA on a new vendor platform. The use of motion correction, types of post-processing softwares and approaches, the type and dose of gadolinium contrast, histological dyes, reading methods, etc., may all influence the measurements. The severity of myocardial damage can vary considerably between the patients included at the different sites; which in such small samples may be a major factor. Although the biopsies were performed during open-heart surgery, inclusion of replacement fibrosis during the tissue sampling is difficult to control. This complication of human EMBs in introducing the sampling errors is also well recognized.32,35 We strived for exclusion of LGE given our strong focus on to the diffuse myocardial disease, yet, we acknowledge that definition of ‘diffuse’ will depend on the spatial resolution of the LGE technique allowing to differentiate localized patterns of fibrosis from the remaining tissue, unlike averaging them within one voxel. The post-processing approach in studies that have not accounted for the regional variations or inadvertent inclusion of blood partial volume in myocardial T1 values,30,31,36 may reveal different results than in the studies using conservative septal ROI.15,26,37 The discriminatory power of ECV values may also suffer from dependency on two separate measurements. Finally, the association between CVF and ECV by MOLLI found in the present study (r = 0.498) compares favourably to the result using tissue FAXS technology33 (r = 0.493). A further interesting finding is the correlation of T1 indices with T2 mapping. This observation communicates an important influence of transverse relaxation, which appears to be captured within the myocardial T1 mapping, consistent with previous reports highlighting the proneness of MOLLI variants to the T2-related errors.20 The effect of magnetization transfer (MT) in MOLLI variants, may be resulting from acquisition of multiple images after each preparation pulse.3,20,38 The difference in FA between implementation of our MOLLI sequence4,10,12 vs. ShMOLLI5 (50° vs. 35°) explains the greater SNR and possibly also the more pronounced T2 and MT effects for MOLLI. Whereas the development of techniques, which are highly accurate for T1 with minimal contamination by T2 or MT or other effects is important for post-contrast T1 acquisitions (i.e. ‘true T1 mapping’), the advantages of the T2-proneness for native T1 mapping—high precision and diagnostic accuracy, yielding higher sensitivity to myocardial pathophysiology, can from the clinical standpoint not be overlooked. Clearly, further research is warranted to elucidate these clinically relevant effects. Lastly, we reveal for the first time that in AS, myocardial native T2 is significantly raised. As it is not significantly associated with myocardial collagen content, it may suggest myocardial oedema.39–42 A body of evidence substantiates the role of inflammatory cellular and extracellular processes in myocardial plasticity and remodelling in response to increased LV wall stress,43,44 including a reactivation of hypertrophic foetal gene programme with phenotypical expression of natriuretic peptides, such as NT-pro BNP, which was also found elevated in the present study.44–47 Increased hs-troponin and CRP levels and relationship with T1 and T2 indices in AS patients may lend a further support to the notion that myocardial oedema, alongside interstitial fibrosis,48 represents a detectable process in extracellular matrix remodelling in hypertrophic cardiac conditions. Study limitations A few limitations apply. This is a single centre, single-vendor and single field-strength comparison study in a sample size, which is based on the previous studies using the identical MOLLI sequence.12 EMBs were performed within the conservative constraints of ethical approval for an invasive procedure performed purely for research purposes. We strived to include a sufficient number of patients required to achieve a significant correlation for native T1 with MOLLI sequence (type I error; α < 0.05) (Type II error; β = 0.8; n = 8), which was also reconfirmed by a posthoc analysis. However, the sample size was not powered to inform on the superiority of correlations between the mapping techniques. The study-design, i.e. head-to-head comparison, and standardized approach to imaging and histology obtained within the same subject, eliminates several important methodological biases, which make comparisons between studies using single techniques difficult. We believe that our results provide a useful guide to the type of much needed evidence, required to support an informed clinical use of T1 mapping sequences. Conclusions We demonstrate that T1 mapping indices and sequences differ in their bioequivalence for detection of abnormal myocardium, which is characterized by diffuse interstitial myocardial fibrosis. Native T1 with MOLLI sequences provides the strongest discriminatory accuracy in characterization of human myocardium. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgments We would like to acknowledge the support of Cardiology and Cardiothoracic Surgery departments at Guy’s and St Thomas’ and King’s College Hospitals NHST Trusts; cardiac radiographers for obtaining the high-quality imaging studies; Philips Clinical Scientists for support: David M. Higgins, PhD; Bernhard Schnackenburg, PhD; Christian Stehning, PhD; Eltjo Haselhoff, PhD. Funding Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. Histological comparisons in aortic stenosis patients were supported by Medical Research Council - Confidence in Concept 2012’ administered through King’s Health Partners project grant (MRJBACR). N.C. was funded by an educational grant from St. Jude Medical. VP, EN, SD, MR-M are supported by the German Centre of Cardiovascular Research (DZHK). Conflict of interest: None declared. References 1 Puntmann VO, Peker E, Chandrashekhar Y, Nagel E. T1 mapping in characterizing myocardial disease. Circ Res  2016; 119: 277– 99. Google Scholar CrossRef Search ADS PubMed  2 Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. 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J Cardiovasc Magn Reson  2014; 16: 2. http://dx.doi.org/10.1186/1532-429X-16-2 Google Scholar CrossRef Search ADS PubMed  21 Flett AS, Hayward MP, Ashworth MT, Hansen MS, Taylor AM, Elliott PM et al.   Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation  2010; 122: 138– 44. Google Scholar CrossRef Search ADS PubMed  22 Bull S, White SK, Piechnik SK, Flett AS, Ferreira VM, Loudon M et al.   Human non-contrast T1 values and correlation with histology in diffuse fibrosis. Heart  2013; 99: 932– 7. Google Scholar CrossRef Search ADS PubMed  23 Fontana M, White SK, Banypersad SM, Sado DM, Maestrini V, Flett AS et al.   Comparison of T1 mapping techniques for ECV quantification. Histological validation and reproducibility of ShMOLLI versus multibreath-hold T1 quantification equilibrium contrast CMR. J Cardiovasc Magn Reson  2012; 14: 88. Google Scholar CrossRef Search ADS PubMed  24 White SK, Sado DM, Fontana M, Banypersad SM, Maestrini V, Flett AS et al.   T1 mapping for myocardial extracellular volume measurement by CMR. JACC Cardiovasc Imaging  2013; 6: 955– 62. Google Scholar CrossRef Search ADS PubMed  25 de Meester de Ravenstein C, Bouzin C, Lazam S, Boulif J, Amzulescu M, Melchior J et al.   Histological validation of measurement of diffuse interstitial myocardial fibrosis by myocardial extravascular volume fraction from Modified Look-Locker imaging (MOLLI) T1 mapping at 3 T. J Cardiovasc Magn Reson  2015; 17: 1268. Google Scholar CrossRef Search ADS   26 Lee S-P, Lee W, Lee JM, Park E-A, Kim H-K, Kim Y-J et al.   Assessment of diffuse myocardial fibrosis by using MR imaging in asymptomatic patients with aortic stenosis. Radiology  2015; 274: 359– 69. http://dx.doi.org/10.1148/radiol.14141120 Google Scholar CrossRef Search ADS PubMed  27 Iles L, Pfluger H, Phrommintikul A, Cherayath J, Aksit P, Gupta SN et al.   Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol  2008; 52: 1574– 80. Google Scholar CrossRef Search ADS PubMed  28 Sibley CT, Noureldin RA, Gai N, Nacif MS, Liu S, Turkbey EB et al.   T1 mapping in cardiomyopathy at cardiac MR: comparison with endomyocardial biopsy. Radiology  2012; 265: 724– 32. Google Scholar CrossRef Search ADS PubMed  29 Mascherbauer J, Marzluf BA, Tufaro C, Pfaffenberger S, Graf A, Wexberg P et al.   Cardiac magnetic resonance postcontrast T1 time is associated with outcome in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging  2013; 6: 1056– 65. 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Google Scholar CrossRef Search ADS PubMed  46 Frey N, Olson EN, Hill JA. Mechanisms of stress-induced cardiac hypertrophy. In: Muscle . Elsevier; 2012. p 481– 94. Google Scholar CrossRef Search ADS   47 Lazzeroni D, Rimoldi O, Camici PG. From left ventricular hypertrophy to dysfunction and failure. Circ J  2016; 80: 555– 64. http://dx.doi.org/10.1253/circj.CJ-16-0062 Google Scholar CrossRef Search ADS PubMed  48 Dimmeler S, Zeiher AM. Netting insights into fibrosis. N Engl J Med  2017; 376: 1475– 7. http://dx.doi.org/10.1056/NEJMcibr1616598 Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

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Abstract

Abstract Aims To determine the bioequivalence of several T1 mapping sequences in myocardial characterization of diffuse myocardial fibrosis. Methods and results We performed an intra-individual sequence comparison of three types of T1 mapping sequences [MOdified Look-Locker Inversion recovery (MOLLI), Shortened MOdified Look-Locker Inversion recovery ((sh)MOLLI), and SAturation recovery single-SHot Acquisition (SASHA)]. We employed two model diseases of diffuse interstitial fibrosis [patients with non-ischaemic dilated cardiomyopathy (NIDCM), n = 32] and aortic stenosis [(AS), n = 25)]. Twenty-six healthy individuals served as controls. Relationship with collagen volume fraction (CVF) was assessed using endomyocardial biopsies (EMB) intraoperatively in 12 AS patients. T2 mapping (GraSE) was also performed. Myocardial native T1 with MOLLI and shMOLLI showed, firstly, an excellent discriminatory accuracy between health and disease [area under the curves (P-value): 0.94 (0.88–0.99); 0.87 (0.79–0.94); 0.61 (0.49–0.72)], secondly, relationship between histological CVF [native T1 MOLLI vs. shMOLLI vs. SASHA: r = 0.582 (P = 0.027), r = 0.524 (P = 0.046), r = 0.443 (P = 0.150)], and thirdly, with native T2 [r = 0.628(P < 0.001), r = 0.459 (P = 0.003), r = 0.211 (P = 0.083)]. The respective relationships for extracellular volume fraction with CVF [r = 0.489 (P = 0.044), r = 0.417 (0.071), r = 0.353 (P = 0.287)] were significant for MOLLI, but not other sequences. In AS patients, native T2 was significantly higher compared to controls, and associated with levels of C-reactive protein and troponin. Conclusion T1 mapping sequences differ in their bioequivalence for discrimination between health and disease as well as associations with diffuse myocardial fibrosis. T1 mapping , MOLLI , shMOLLI , SASHA , collagen Introduction Myocardial T1 mapping provides a novel concept in quantitative tissue characterization, yielding a value, unlike relying on visually recognizable contrast differences. Thus, T1 mapping measurements can be used to relay biologically important properties in a quantitative manner, including the presence and severity of abnormal myocardium in many cardiac conditions. T1 indices have a potential to improve clinical diagnosis and risk stratification, particularly in conditions with diffuse myocardial involvement.1 Despite the surge in evidence, the immediate clinical translation of these techniques is complicated by multiple variants of similar T1 mapping sequences. Each sequence and its modification yield different normal values and ranges, and show variable diagnostic performance in detection of abnormalities in human myocardium. Thus, each sequence will represent an individual diagnostic test, necessitating an individual clinical validation and standardization.2 T1 mapping sequences employed in myocardial characterization differ principally in magnetization preparation by either an inversion recovery (IR) or a saturation recovery (SR) prepulse (reviewed in Higgins et al.3) The many variants of these two approaches are further distinguished by different schemes of image acquisition (e.g. number of prepulses/images/pauses) and readout parameters [flip angle (FA), time delay, adiabatic prepulse, etc]. The sequence most commonly reported is based on the IR sequence MOdified Look-Locker (MOLLI). Following its original publication,4 numerous MOLLI variants have been developed either to achieve shorter breath-holds5,6 or greater T1 accuracy.7 SR sequences benefit from a much shorter period of T1 relaxation following a SR preparation8,9 and absence of history of magnetization of prior heartbeats, thus, shortening the overall acquisition time and improving the T1 accuracy, respectively. All T1 mapping methods are continuously and actively modified (‘optimized’) in terms of protocol parameters, scanner software versions, practical scanning methodology and methods of analysis, as well as manufacturer-specific implementations. In this study, we undertook sequence comparison of the 3 most commonly reported T1 mapping sequences—within the same individual—to examine their bioequivalence, or performance in vivo, in terms of diagnostic accuracy, relationships with histologically derived collagen volume fraction (CVF), and their T2 sensitivity by comparison with T2 mapping, in two model diseases of diffuse myocardial fibrosis; non-ischaemic dilative cardiomyopathy (NIDCM) and aortic stenosis (AS). Methods Consecutive patients from Guys and St. Thomas’ and Kings College Hospitals were invited to participate in this study: Patients with NIDCM10 (n = 32). Prior to their enrolment, the diagnosis was confirmed by cardiovascular magnetic resonance (CMR) on the basis of increased LV end-diastolic volume indexed to body surface area and reduced LV ejection fraction (EF < 50%) compared with published reference ranges normalized for age and sex.11 Several of these subjects were included in our previous publications.10,12,13 Patients with severe AS (n = 25) were identified from cardiology and cardiothoracic surgery outpatient clinics. AS was the leading valve problem based on Doppler echocardiographic demonstration of mean aortic valve pressure gradient >40 mmHg.14 Asymptomatic and normotensive subjects (n = 26), taking no regular medication and with no significant medical history and normal CMR findings, including volumes and mass, served as controls.12,15 Control subjects were recruited as a part of the parallel project into the normal values.16 The subgroup was selected to provide an age-gender matched control group to the AS group.Exclusion criteria for all subjects are detailed in supplementary material. Blood samples for haematocrit in AS patients were obtained contemporaneously at the time of the CMR procedure, whereas in patients with NIDCM these were based on the clinical blood tests.10 Analysis of serological cardiac biomarkers, including N-terminal-pro brain natriuretic peptide (NT-BNP), type 1 procollagen C-terminal propeptide (PICP), high-sensitive (hs-) troponin and hs-C-reactive protein (CRP), was performed using commercial platforms. The study protocol was reviewed and approved by the local ethics committee, and written informed consent was obtained from all participants. All procedures were carried out in accordance with the Declaration of Helsinki (2013). Image acquisition and analysis All sequence parameters are detailed in the Supplementary material. Subjects underwent a routine clinical protocol for cardiac volumes and mass (with cine imaging) and tissue characterization with T1 mapping and late gadolinium enhancement (LGE) imaging using 3-Tesla MRI scanner equipped with advanced cardiac package and multi-transmit technology (Achieva, Philips Healthcare, Best, The Netherlands).10,12,17 T1 mapping was performed using two MOLLI variants [the original MOLLI4,10,12 and Shortened MOdified Look-Locker Inversion recovery (shMOLLI)5] and a SR variant, SAturation recovery single-SHot Acquisition (SASHA).8 Sequences were acquired in random order (to avoid bias) in a single midventricular short axis (SAX) slice, prior to and 15 minutes after intravenous administration of gadobutrol (0.2 mmol/kg per body weight, Gadovist®, Bayer Healthcare, Leverkusen, Germany). T2 mapping was performed in the same geometry using a hybrid gradient and spin echo GraSE sequence. CMR analysis was performed using commercially available software (CVI42®, Circle Cardiovascular Imaging Ltd, Calgary, Canada) following standardized post-processing recommendations.10,18 LGE images were visually examined for the presence of regional scar tissue in two phase-encoding directions and confirmed as positive if the visually positive regions had a SI > 4 standard deviations (SD) from normal regions.17 Recovery rate of T1 and T2 relaxation for all sequences was measured conservatively within the septal myocardium, using PRIDE (Philips, Best, The Netherlands), as previously described and validated.12,15 Areas of LGE were excluded from the mapping regions of interests (ROI). Care was taken to avoid contamination of myocardial signal with the blood pool. In addition to T1-values of native and post-contrast myocardium the gadolinium extracellular partition coefficient, the haematocrit-corrected extracellular volume fraction (ECV) was calculated.19 Myocardial biopsies and histological analysis Several (n ≥ 3 per person) intraoperative deep endomyocardial biopsy (EMB) samples were obtained in 12 AS patients using either biopsy forceps (Novatome, Scholten®) or direct surgical excision, as per choice of operator. EMBs were sampled from the mid-portion of the interventricular septum, avoiding the basal fibrotic membranous part. Sample preparation and analysis approach are described in supplementary material. Mean percent fibrosis (CVF), fibrosis heterogeneity (SD between fields), patient heterogeneity (interquartile range, IQR), and inter-observer coefficient of variation (CoV) are reported. Statistical analysis Statistical analysis was performed using SPSS software (SPSS Inc., Chicago, IL, USA, version 23.0). Normality of distributions was tested using Wilks-Shapiro statistic. Categorical data are expressed as percentages, and continuous variables as mean ± SD or median (interquartile range), as appropriate. Comparisons of the means between groups were performed using one way ANOVA (with Bonferroni posthoc tests for the differences from controls). Associations between variables were detected by bivariate linear regression analyses. Repeatability of measurements were assessed using intraclass-correlations (ICC). Receiver operating characteristic (ROC) curves was used in discrimination between health and disease. All values are reported as mean±SD and a P-value of less than 0.05 was considered statistically significant. Results A total of 83 subjects completed the imaging protocol with the 3 T1 mapping sequences. Subject characteristics and CMR results are presented in Supplementary data online, Table S1. Groups were similar for age, gender, heart rate and diastolic blood pressure, whereas the body-mass index and systolic BP were significantly higher in AS patients. Compared to controls, both patient groups had significantly higher indexed left ventricular (LV) volumes, LV mass, left atrial size, and lower LV and RV ejection fraction (P < 0.05 for all). All patients with AS has increased LV wall thickness ≥12 mm, measured in diastole. Non-ischaemic LGE was present in a total of 10 NIDCM (31%) and 5 AS (20%) patients. Patients had significantly higher mean E/e′ on transthoracic echocardiography, as well as the levels of serological cardiac biomarkers. Native T1 and ECV data show progressively larger imprecision and variation in normal controls from MOLLI to ShMOLLI to SASHA (see Supplementary data online, Table S2).9,20 Compared with controls, native T1 and ECV were significantly higher in both patient groups for MOLLI and shMOLLI sequences (P < 0.01), whereas SASHA only revealed a significant difference between controls and patients with NIDCM. Post-contrast T1 values were significantly different for the MOLLI sequence but not shMOLLI or SASHA (Table 2). Native T2 was raised in NIDCM and AS patients, significantly in the latter group. Table 2 Summary of studies reporting on association between CVF and T1 mapping indices modified and adapted from1 (with permission) Collagen volume fraction%  Sequence  Pearson r (Sig)  No. of patients (cardiac disease)  GCAs (dose and type)  T1 Index  Histological staining  Aortic stenosis               Flett et al.21  GRE-IR  0.94 (0.001)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red   Bull et al.22  shMOLLI  0.655 (0.002)  19    Native T1  Picrosirius red   Fontana et al.23  GRE-IR  0.78 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red    shMOLLI  0.83 (<0.01)     White et al.24  shMOLLI  0.83 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (bolus)  Picrosirius red  0.84 (<0.01)  ECV (EQ)   de Meester de Ravenstein et al.25  MOLLI 3(3)3(3)5 (FA35°)  −0.15 (0.64)  12  (0.2 mmol/kg gadobutrol)  Native T1  Picrosirius red  −0.64 (0.024)    Post-contrast T1  0.91 (0.001)    ECV   Lee et al.26  MOLLI 3(3)3(3)5(FA35°)  0.77 (<0.01)  10    Native T1  Picrosirius red  Child  MOLLI 3(2)3(2)5(FA50°)  0.582 (0.027)  12  (0.2 mmol/kg gadobutrol)  Native T1  Masson-trichrome  −0.47 (0.065)  Post-contrast T1  0.498 (0.044)  ECV  shMOLLI  0.524 (0.046)  Native T1  −0.45 (0.140)  Post-contrast T1  0.417 (0.071)  ECV  SASHA  0.442 (0.150)  Native T1  −0.27 (0.411)  Post-contrast T1  0.353 (0.287)  ECV  Heart failure               Iles et al.27  VAST  −0.7 (0.03)  9 (IHD)  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Picrosirius red   Sibley et al.28  Look-Locker  −0.57 (<0.001)  47 (NICMs)  (0.2 mmol/kg gadodiamide)  Post-contrast T1  Masson trichrome   Mascherbauer et al.29  GRE-IR  −0.98 (<0.01)  9 (HFpPEF)  (0.2 mmol/kg gadobutrol)  Post-contrast T1  Masson Trichrome/Congo-red   Miller et al.30  MOLLI 3(3)3(3)5(FA 35°)  0.199 (0.437)  6 (IHD)  (0.2 mmol/kg (gadopentetate dimeglumine)  Native T1  Picrosirius red    −0.21 (0.69)  Post-contrast T1    0.945 (0.004)  ECV (bolus)   Aus dem Siepen et al.31  MOLLI 3(3)3(3)5(FA 35°)  0.85 (0.01)  45 (DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  ECV (bolus)  Acid Fuchsin Orange-G   Iles et al.32  VAST  0.73 (<0.001)  4 (1 IHD, 3 DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  LGE  Masson Trichrome    −0.64 (0.002)  Post-contrast T1   Kammerlander et al.33  MOLLI 5(3)3 (FA 35°) for native acquisition  0.493 (<0.002)  36 (mixed group)  (0.1 mmol/kg of gadobutrol)  ECV (bolus)  Tissue FAXS  MOLLI 4(1)3(1)2(FA 35°) for post-contrast acquisition  Hypertrophic cardiomyopathy               Flett et al.21  GRE-IR  R2 = 0.62(0.08), Tau = 0.52  8  (0.2 mmol/kg gadoterate meglumine)  ECV  Picrosirius red   Iles et al.32  VAST  −0.71 (0.01)  8  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Masson-trichrome  Collagen volume fraction%  Sequence  Pearson r (Sig)  No. of patients (cardiac disease)  GCAs (dose and type)  T1 Index  Histological staining  Aortic stenosis               Flett et al.21  GRE-IR  0.94 (0.001)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red   Bull et al.22  shMOLLI  0.655 (0.002)  19    Native T1  Picrosirius red   Fontana et al.23  GRE-IR  0.78 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red    shMOLLI  0.83 (<0.01)     White et al.24  shMOLLI  0.83 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (bolus)  Picrosirius red  0.84 (<0.01)  ECV (EQ)   de Meester de Ravenstein et al.25  MOLLI 3(3)3(3)5 (FA35°)  −0.15 (0.64)  12  (0.2 mmol/kg gadobutrol)  Native T1  Picrosirius red  −0.64 (0.024)    Post-contrast T1  0.91 (0.001)    ECV   Lee et al.26  MOLLI 3(3)3(3)5(FA35°)  0.77 (<0.01)  10    Native T1  Picrosirius red  Child  MOLLI 3(2)3(2)5(FA50°)  0.582 (0.027)  12  (0.2 mmol/kg gadobutrol)  Native T1  Masson-trichrome  −0.47 (0.065)  Post-contrast T1  0.498 (0.044)  ECV  shMOLLI  0.524 (0.046)  Native T1  −0.45 (0.140)  Post-contrast T1  0.417 (0.071)  ECV  SASHA  0.442 (0.150)  Native T1  −0.27 (0.411)  Post-contrast T1  0.353 (0.287)  ECV  Heart failure               Iles et al.27  VAST  −0.7 (0.03)  9 (IHD)  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Picrosirius red   Sibley et al.28  Look-Locker  −0.57 (<0.001)  47 (NICMs)  (0.2 mmol/kg gadodiamide)  Post-contrast T1  Masson trichrome   Mascherbauer et al.29  GRE-IR  −0.98 (<0.01)  9 (HFpPEF)  (0.2 mmol/kg gadobutrol)  Post-contrast T1  Masson Trichrome/Congo-red   Miller et al.30  MOLLI 3(3)3(3)5(FA 35°)  0.199 (0.437)  6 (IHD)  (0.2 mmol/kg (gadopentetate dimeglumine)  Native T1  Picrosirius red    −0.21 (0.69)  Post-contrast T1    0.945 (0.004)  ECV (bolus)   Aus dem Siepen et al.31  MOLLI 3(3)3(3)5(FA 35°)  0.85 (0.01)  45 (DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  ECV (bolus)  Acid Fuchsin Orange-G   Iles et al.32  VAST  0.73 (<0.001)  4 (1 IHD, 3 DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  LGE  Masson Trichrome    −0.64 (0.002)  Post-contrast T1   Kammerlander et al.33  MOLLI 5(3)3 (FA 35°) for native acquisition  0.493 (<0.002)  36 (mixed group)  (0.1 mmol/kg of gadobutrol)  ECV (bolus)  Tissue FAXS  MOLLI 4(1)3(1)2(FA 35°) for post-contrast acquisition  Hypertrophic cardiomyopathy               Flett et al.21  GRE-IR  R2 = 0.62(0.08), Tau = 0.52  8  (0.2 mmol/kg gadoterate meglumine)  ECV  Picrosirius red   Iles et al.32  VAST  −0.71 (0.01)  8  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Masson-trichrome  Types of sequences and a staining method used, as well as numbers of patients included, is also reported. GCAs, gadolinium contrast agents, IHD, ischaemic heart disease; HFpEF, heart failure with preserved ejection fraction; NICM, non-ischaemic cardiomyopathy; GRE-IR, gradient echo-inversion recovery; VAST, variable sampling of k-space in time. Table 2 Summary of studies reporting on association between CVF and T1 mapping indices modified and adapted from1 (with permission) Collagen volume fraction%  Sequence  Pearson r (Sig)  No. of patients (cardiac disease)  GCAs (dose and type)  T1 Index  Histological staining  Aortic stenosis               Flett et al.21  GRE-IR  0.94 (0.001)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red   Bull et al.22  shMOLLI  0.655 (0.002)  19    Native T1  Picrosirius red   Fontana et al.23  GRE-IR  0.78 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red    shMOLLI  0.83 (<0.01)     White et al.24  shMOLLI  0.83 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (bolus)  Picrosirius red  0.84 (<0.01)  ECV (EQ)   de Meester de Ravenstein et al.25  MOLLI 3(3)3(3)5 (FA35°)  −0.15 (0.64)  12  (0.2 mmol/kg gadobutrol)  Native T1  Picrosirius red  −0.64 (0.024)    Post-contrast T1  0.91 (0.001)    ECV   Lee et al.26  MOLLI 3(3)3(3)5(FA35°)  0.77 (<0.01)  10    Native T1  Picrosirius red  Child  MOLLI 3(2)3(2)5(FA50°)  0.582 (0.027)  12  (0.2 mmol/kg gadobutrol)  Native T1  Masson-trichrome  −0.47 (0.065)  Post-contrast T1  0.498 (0.044)  ECV  shMOLLI  0.524 (0.046)  Native T1  −0.45 (0.140)  Post-contrast T1  0.417 (0.071)  ECV  SASHA  0.442 (0.150)  Native T1  −0.27 (0.411)  Post-contrast T1  0.353 (0.287)  ECV  Heart failure               Iles et al.27  VAST  −0.7 (0.03)  9 (IHD)  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Picrosirius red   Sibley et al.28  Look-Locker  −0.57 (<0.001)  47 (NICMs)  (0.2 mmol/kg gadodiamide)  Post-contrast T1  Masson trichrome   Mascherbauer et al.29  GRE-IR  −0.98 (<0.01)  9 (HFpPEF)  (0.2 mmol/kg gadobutrol)  Post-contrast T1  Masson Trichrome/Congo-red   Miller et al.30  MOLLI 3(3)3(3)5(FA 35°)  0.199 (0.437)  6 (IHD)  (0.2 mmol/kg (gadopentetate dimeglumine)  Native T1  Picrosirius red    −0.21 (0.69)  Post-contrast T1    0.945 (0.004)  ECV (bolus)   Aus dem Siepen et al.31  MOLLI 3(3)3(3)5(FA 35°)  0.85 (0.01)  45 (DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  ECV (bolus)  Acid Fuchsin Orange-G   Iles et al.32  VAST  0.73 (<0.001)  4 (1 IHD, 3 DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  LGE  Masson Trichrome    −0.64 (0.002)  Post-contrast T1   Kammerlander et al.33  MOLLI 5(3)3 (FA 35°) for native acquisition  0.493 (<0.002)  36 (mixed group)  (0.1 mmol/kg of gadobutrol)  ECV (bolus)  Tissue FAXS  MOLLI 4(1)3(1)2(FA 35°) for post-contrast acquisition  Hypertrophic cardiomyopathy               Flett et al.21  GRE-IR  R2 = 0.62(0.08), Tau = 0.52  8  (0.2 mmol/kg gadoterate meglumine)  ECV  Picrosirius red   Iles et al.32  VAST  −0.71 (0.01)  8  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Masson-trichrome  Collagen volume fraction%  Sequence  Pearson r (Sig)  No. of patients (cardiac disease)  GCAs (dose and type)  T1 Index  Histological staining  Aortic stenosis               Flett et al.21  GRE-IR  0.94 (0.001)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red   Bull et al.22  shMOLLI  0.655 (0.002)  19    Native T1  Picrosirius red   Fontana et al.23  GRE-IR  0.78 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (EQ)  Picrosirius red    shMOLLI  0.83 (<0.01)     White et al.24  shMOLLI  0.83 (<0.01)  18  (0.2 mmol/kg gadoterate meglumine)  ECV (bolus)  Picrosirius red  0.84 (<0.01)  ECV (EQ)   de Meester de Ravenstein et al.25  MOLLI 3(3)3(3)5 (FA35°)  −0.15 (0.64)  12  (0.2 mmol/kg gadobutrol)  Native T1  Picrosirius red  −0.64 (0.024)    Post-contrast T1  0.91 (0.001)    ECV   Lee et al.26  MOLLI 3(3)3(3)5(FA35°)  0.77 (<0.01)  10    Native T1  Picrosirius red  Child  MOLLI 3(2)3(2)5(FA50°)  0.582 (0.027)  12  (0.2 mmol/kg gadobutrol)  Native T1  Masson-trichrome  −0.47 (0.065)  Post-contrast T1  0.498 (0.044)  ECV  shMOLLI  0.524 (0.046)  Native T1  −0.45 (0.140)  Post-contrast T1  0.417 (0.071)  ECV  SASHA  0.442 (0.150)  Native T1  −0.27 (0.411)  Post-contrast T1  0.353 (0.287)  ECV  Heart failure               Iles et al.27  VAST  −0.7 (0.03)  9 (IHD)  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Picrosirius red   Sibley et al.28  Look-Locker  −0.57 (<0.001)  47 (NICMs)  (0.2 mmol/kg gadodiamide)  Post-contrast T1  Masson trichrome   Mascherbauer et al.29  GRE-IR  −0.98 (<0.01)  9 (HFpPEF)  (0.2 mmol/kg gadobutrol)  Post-contrast T1  Masson Trichrome/Congo-red   Miller et al.30  MOLLI 3(3)3(3)5(FA 35°)  0.199 (0.437)  6 (IHD)  (0.2 mmol/kg (gadopentetate dimeglumine)  Native T1  Picrosirius red    −0.21 (0.69)  Post-contrast T1    0.945 (0.004)  ECV (bolus)   Aus dem Siepen et al.31  MOLLI 3(3)3(3)5(FA 35°)  0.85 (0.01)  45 (DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  ECV (bolus)  Acid Fuchsin Orange-G   Iles et al.32  VAST  0.73 (<0.001)  4 (1 IHD, 3 DCM)  (0.2 mmol/kg gadopentetate dimeglumine)  LGE  Masson Trichrome    −0.64 (0.002)  Post-contrast T1   Kammerlander et al.33  MOLLI 5(3)3 (FA 35°) for native acquisition  0.493 (<0.002)  36 (mixed group)  (0.1 mmol/kg of gadobutrol)  ECV (bolus)  Tissue FAXS  MOLLI 4(1)3(1)2(FA 35°) for post-contrast acquisition  Hypertrophic cardiomyopathy               Flett et al.21  GRE-IR  R2 = 0.62(0.08), Tau = 0.52  8  (0.2 mmol/kg gadoterate meglumine)  ECV  Picrosirius red   Iles et al.32  VAST  −0.71 (0.01)  8  (0.2 mmol/kg gadopentetate dimeglumine)  Post-contrast T1  Masson-trichrome  Types of sequences and a staining method used, as well as numbers of patients included, is also reported. GCAs, gadolinium contrast agents, IHD, ischaemic heart disease; HFpEF, heart failure with preserved ejection fraction; NICM, non-ischaemic cardiomyopathy; GRE-IR, gradient echo-inversion recovery; VAST, variable sampling of k-space in time. ROC curves in discrimination between health and disease (all patients) are presented in Figure 1, with respective area under the curves [(AUCs), 95% confidence interval (95% CI)] for all T1 mapping indices and sequences listed in Table 1. Native T1 for MOLLI showed the greatest ability to discriminate between health and disease [AUC: 0.94 (0.88–0.99), P < 0.001; comparisons of AUCs: MOLLI vs. shMOLLI, SASHA and T2: P = 0.064, P < 0.001, P = 0.01, respectively]. Native T2 also showed a strong ability to differentiate between health and disease [AUC: 0.81 (0.73–0.89), P < 0.001]. Native T1 by MOLLI was an independent discriminator between health and disease (χ2 = 52, P < 0.001). Table 1 Discrimination between health and disease   Native T1    Post-contrast T1    ECV    Controls vs. all patients  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  MOLLI  0.94 (0.88–0.99)  <0.001  0.66 (0.54–0.77)  0.005  0.73 (0.64–0.83)  <0.001  ShMOLLI  0.87 (0.79–0.94)  <0.001  0.64 (0.52–0.75)  0.02  0.67 (0.58–0.79)  <0.001  SASHA  0.61 (0.49–0.72)  0.067  0.62 (0.50–0.73)  0.04  0.59 (0.46–0.72)  0.02  Native T2  0.81 (0.73–0.89)  <0.001  /  /  /  /    Native T1    Post-contrast T1    ECV    Controls vs. all patients  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  MOLLI  0.94 (0.88–0.99)  <0.001  0.66 (0.54–0.77)  0.005  0.73 (0.64–0.83)  <0.001  ShMOLLI  0.87 (0.79–0.94)  <0.001  0.64 (0.52–0.75)  0.02  0.67 (0.58–0.79)  <0.001  SASHA  0.61 (0.49–0.72)  0.067  0.62 (0.50–0.73)  0.04  0.59 (0.46–0.72)  0.02  Native T2  0.81 (0.73–0.89)  <0.001  /  /  /  /  The comparative performance of each sequence to discriminate between health and disease controls and all patients) for native T1, post-contrast T1 and ECV, using ROC-curve analysis to derive AUC. Table 1 Discrimination between health and disease   Native T1    Post-contrast T1    ECV    Controls vs. all patients  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  MOLLI  0.94 (0.88–0.99)  <0.001  0.66 (0.54–0.77)  0.005  0.73 (0.64–0.83)  <0.001  ShMOLLI  0.87 (0.79–0.94)  <0.001  0.64 (0.52–0.75)  0.02  0.67 (0.58–0.79)  <0.001  SASHA  0.61 (0.49–0.72)  0.067  0.62 (0.50–0.73)  0.04  0.59 (0.46–0.72)  0.02  Native T2  0.81 (0.73–0.89)  <0.001  /  /  /  /    Native T1    Post-contrast T1    ECV    Controls vs. all patients  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  AUC (95% CI)  Sig (P-value)  MOLLI  0.94 (0.88–0.99)  <0.001  0.66 (0.54–0.77)  0.005  0.73 (0.64–0.83)  <0.001  ShMOLLI  0.87 (0.79–0.94)  <0.001  0.64 (0.52–0.75)  0.02  0.67 (0.58–0.79)  <0.001  SASHA  0.61 (0.49–0.72)  0.067  0.62 (0.50–0.73)  0.04  0.59 (0.46–0.72)  0.02  Native T2  0.81 (0.73–0.89)  <0.001  /  /  /  /  The comparative performance of each sequence to discriminate between health and disease controls and all patients) for native T1, post-contrast T1 and ECV, using ROC-curve analysis to derive AUC. Figures 1 View largeDownload slide Native T1 (A), post-contrast T1 (B), and ECV (C) in discrimination between health and disease for three sequences in all patients against healthy controls using ROC curve analysis. Figures 1 View largeDownload slide Native T1 (A), post-contrast T1 (B), and ECV (C) in discrimination between health and disease for three sequences in all patients against healthy controls using ROC curve analysis. Results of myocardial histology and associations with T1 mapping indices are presented in Table 2 (Figures 2 and 3). Procedurally, all EMBs were uneventful (n = 12). The mean histological CVF was 25.6% (intersubject IQR 10.1–43.2%, SD 18.6). There was an excellent agreement between the two observers (r = 0.95, P < 0.01; MD ± SD = 5.9 ± 4.6). Correlations between CVF with all T1 mapping indices for various sequences are included in Table 2 (Figure 4). There was moderate significant association for native T1 with MOLLI and shMOLLI, whereas correlation with SASHA was not significant. For ECV only MOLLI showed a significant association. Native T2 showed a mild but not significant association with CVF (r = 0.271, P = 0.24). Table 3 summarizes the correlations with serological markers for all T1 mapping indices in AS and NIDCM patients. Native T1 with MOLLI and shMOLLI, post-contrast T1 with MOLLI, and native T2 showed significant associations with N-terminal prohormone of brain natriuretic peptide (NT-proBNP), hs-troponin and CRP, but not PICP. Repeatability of measurements (ICCs) are reported in Supplementary Material. Table 3 Correlations between T1 and T2 mapping indices and serological markers in AS patients (n = 25) using Pearson correlation (r-statistic)   AS patients (n = 25)   NIDCM patients (n = 34)     T2 mapping (ms)  NT-proBNP  hs-Troponin  hs-CRP  PICP  NT-proBNP  hs-Troponin  hs-CRP  PICP  MOLLI                     Native T1 (ms)  0.628**  0.404*  0.324*  0.550**  0.284  0.441*  0.145  0.362*  0.316   Post-contrast T1 (ms)  −0.22  −0.470*  −0.334  −0.351*  −0.091  −0.328  −0.122  −0.291  −0.172   ECV (%)  0.248*  0.327  0.272  0.216  0.070  0.315  0.171  0.226  0.231  ShMOLLI                     Native T1 (ms)  0.459**  0.379*  0.217  0.409*  0.32  0.427*  0.160  0.350*  0.293   Post-contrast T1 (ms)  −0.16  −0.311  −0.201  −0.308  −0.19  −0.247  −0.114  −0.314  −0.189   ECV (%)  0.236*  0.234  0.195  0.142  0.068  0.285  0.125  0.164  0.193  SASHA                     Native T1 (ms)  0.211  0.095  0.099  0.213  0.083  0.136  0.083  0.291  0.233   Post-contrast T1 (ms)  0.027  −0.055  −0.025  −0.139  −0.069  −0.049  −0.053  −0.129  −0.061   ECV (%)  0.471  0.032  0.112  0.217  0.134  0.047  0.193  0.116  0.053  Native T2    0.414*  0.366*  0.382*  0.118  0.362*  0.162  0.351*  0.148    AS patients (n = 25)   NIDCM patients (n = 34)     T2 mapping (ms)  NT-proBNP  hs-Troponin  hs-CRP  PICP  NT-proBNP  hs-Troponin  hs-CRP  PICP  MOLLI                     Native T1 (ms)  0.628**  0.404*  0.324*  0.550**  0.284  0.441*  0.145  0.362*  0.316   Post-contrast T1 (ms)  −0.22  −0.470*  −0.334  −0.351*  −0.091  −0.328  −0.122  −0.291  −0.172   ECV (%)  0.248*  0.327  0.272  0.216  0.070  0.315  0.171  0.226  0.231  ShMOLLI                     Native T1 (ms)  0.459**  0.379*  0.217  0.409*  0.32  0.427*  0.160  0.350*  0.293   Post-contrast T1 (ms)  −0.16  −0.311  −0.201  −0.308  −0.19  −0.247  −0.114  −0.314  −0.189   ECV (%)  0.236*  0.234  0.195  0.142  0.068  0.285  0.125  0.164  0.193  SASHA                     Native T1 (ms)  0.211  0.095  0.099  0.213  0.083  0.136  0.083  0.291  0.233   Post-contrast T1 (ms)  0.027  −0.055  −0.025  −0.139  −0.069  −0.049  −0.053  −0.129  −0.061   ECV (%)  0.471  0.032  0.112  0.217  0.134  0.047  0.193  0.116  0.053  Native T2    0.414*  0.366*  0.382*  0.118  0.362*  0.162  0.351*  0.148  P-value of < 0.05 was statistically significant; * P < 0.05 ** P < 0.01. Table 3 Correlations between T1 and T2 mapping indices and serological markers in AS patients (n = 25) using Pearson correlation (r-statistic)   AS patients (n = 25)   NIDCM patients (n = 34)     T2 mapping (ms)  NT-proBNP  hs-Troponin  hs-CRP  PICP  NT-proBNP  hs-Troponin  hs-CRP  PICP  MOLLI                     Native T1 (ms)  0.628**  0.404*  0.324*  0.550**  0.284  0.441*  0.145  0.362*  0.316   Post-contrast T1 (ms)  −0.22  −0.470*  −0.334  −0.351*  −0.091  −0.328  −0.122  −0.291  −0.172   ECV (%)  0.248*  0.327  0.272  0.216  0.070  0.315  0.171  0.226  0.231  ShMOLLI                     Native T1 (ms)  0.459**  0.379*  0.217  0.409*  0.32  0.427*  0.160  0.350*  0.293   Post-contrast T1 (ms)  −0.16  −0.311  −0.201  −0.308  −0.19  −0.247  −0.114  −0.314  −0.189   ECV (%)  0.236*  0.234  0.195  0.142  0.068  0.285  0.125  0.164  0.193  SASHA                     Native T1 (ms)  0.211  0.095  0.099  0.213  0.083  0.136  0.083  0.291  0.233   Post-contrast T1 (ms)  0.027  −0.055  −0.025  −0.139  −0.069  −0.049  −0.053  −0.129  −0.061   ECV (%)  0.471  0.032  0.112  0.217  0.134  0.047  0.193  0.116  0.053  Native T2    0.414*  0.366*  0.382*  0.118  0.362*  0.162  0.351*  0.148    AS patients (n = 25)   NIDCM patients (n = 34)     T2 mapping (ms)  NT-proBNP  hs-Troponin  hs-CRP  PICP  NT-proBNP  hs-Troponin  hs-CRP  PICP  MOLLI                     Native T1 (ms)  0.628**  0.404*  0.324*  0.550**  0.284  0.441*  0.145  0.362*  0.316   Post-contrast T1 (ms)  −0.22  −0.470*  −0.334  −0.351*  −0.091  −0.328  −0.122  −0.291  −0.172   ECV (%)  0.248*  0.327  0.272  0.216  0.070  0.315  0.171  0.226  0.231  ShMOLLI                     Native T1 (ms)  0.459**  0.379*  0.217  0.409*  0.32  0.427*  0.160  0.350*  0.293   Post-contrast T1 (ms)  −0.16  −0.311  −0.201  −0.308  −0.19  −0.247  −0.114  −0.314  −0.189   ECV (%)  0.236*  0.234  0.195  0.142  0.068  0.285  0.125  0.164  0.193  SASHA                     Native T1 (ms)  0.211  0.095  0.099  0.213  0.083  0.136  0.083  0.291  0.233   Post-contrast T1 (ms)  0.027  −0.055  −0.025  −0.139  −0.069  −0.049  −0.053  −0.129  −0.061   ECV (%)  0.471  0.032  0.112  0.217  0.134  0.047  0.193  0.116  0.053  Native T2    0.414*  0.366*  0.382*  0.118  0.362*  0.162  0.351*  0.148  P-value of < 0.05 was statistically significant; * P < 0.05 ** P < 0.01. Figures 2 View largeDownload slide Representative images of patients with AS—Case 1. (A) Histological analysis with Mason Trichrome reveals mild-moderate interstitial fibrosis (CVF = 16%). MOLLI measurement reveal native T1 1068 ms (B) and ECV = 26%. Cine imaging in mid-systole: 3-chamber (C), LVOT (D) view and AV valve view, revealing significantly reduced AV opening (AV area by planimetry 0.56 cm2). There is no evidence of late gadolinium enhancement (F). NTproBNP 634 ng/L. Figures 2 View largeDownload slide Representative images of patients with AS—Case 1. (A) Histological analysis with Mason Trichrome reveals mild-moderate interstitial fibrosis (CVF = 16%). MOLLI measurement reveal native T1 1068 ms (B) and ECV = 26%. Cine imaging in mid-systole: 3-chamber (C), LVOT (D) view and AV valve view, revealing significantly reduced AV opening (AV area by planimetry 0.56 cm2). There is no evidence of late gadolinium enhancement (F). NTproBNP 634 ng/L. Figures 3 View largeDownload slide Representative images of patients with AS—Case 2. (A) Histological analysis with Mason Trichrome reveals considerable myocardial fibrosis (CVF 37%). MOLLI measurement in mid-ventricular SAX slice show native T1 1130 ms (B) and ECV 32%. Cine imaging in mid-systole: 3-chamber (C), LVOT (D) view and AV valve view, reduced AV opening (AV area by planimetry 0.37 cm2). Evidence of non-ischaemic late gadolinium enhancement in basal anteroseptal and inferolateral segments—red arrows (green arrow points to the basal RV structures, including RV outflow tract and pulmonary valve) (F). NTproBNP 1381 ng/L. Figures 3 View largeDownload slide Representative images of patients with AS—Case 2. (A) Histological analysis with Mason Trichrome reveals considerable myocardial fibrosis (CVF 37%). MOLLI measurement in mid-ventricular SAX slice show native T1 1130 ms (B) and ECV 32%. Cine imaging in mid-systole: 3-chamber (C), LVOT (D) view and AV valve view, reduced AV opening (AV area by planimetry 0.37 cm2). Evidence of non-ischaemic late gadolinium enhancement in basal anteroseptal and inferolateral segments—red arrows (green arrow points to the basal RV structures, including RV outflow tract and pulmonary valve) (F). NTproBNP 1381 ng/L. Figure 4 View largeDownload slide Correlations between T1 mapping measurements and histologically derived CVF—native T1 (A–C) and ECV (D–F). Figure 4 View largeDownload slide Correlations between T1 mapping measurements and histologically derived CVF—native T1 (A–C) and ECV (D–F). Discussion We demonstrate that T1 mapping sequences differ considerably in their performance in myocardial tissue characterization, as evidenced by differential ability to discriminate between health and disease and by diverse associations with myocardial CVF and T2 mapping. More specifically, our findings reveal that native T1 using MOLLI sequences show an excellent diagnostic performance in detecting the differences in myocardium between controls and patients. Myocardial T1 mapping with MOLLI sequences showed the strongest relationship with histologically derived CVF and with T2 mapping. A number of previous studies reported on associations with tissue collagen content or discrimination between health and disease (summarized in Figure 4, modified from1) We expand these findings by comprehensive and standardized intraindividual acquisition of more than one sequence and analysis of all T1 indices. Compared with a previous reports we found similar associations for native T1 with CVF for shMOLLI.22 For MOLLI, previous studies reported diverse associations for native T1 and CVF ranging between 0.15 and 0.77,1 and our results add to the favourable side of that range. Associations for ECV, however, were much lower for both shMOLLI23,24 and MOLLI.34 Several possible reasons may explain these findings, especially the type of sequences, given the implementation and optimization of shMOLLI and SASHA on a new vendor platform. The use of motion correction, types of post-processing softwares and approaches, the type and dose of gadolinium contrast, histological dyes, reading methods, etc., may all influence the measurements. The severity of myocardial damage can vary considerably between the patients included at the different sites; which in such small samples may be a major factor. Although the biopsies were performed during open-heart surgery, inclusion of replacement fibrosis during the tissue sampling is difficult to control. This complication of human EMBs in introducing the sampling errors is also well recognized.32,35 We strived for exclusion of LGE given our strong focus on to the diffuse myocardial disease, yet, we acknowledge that definition of ‘diffuse’ will depend on the spatial resolution of the LGE technique allowing to differentiate localized patterns of fibrosis from the remaining tissue, unlike averaging them within one voxel. The post-processing approach in studies that have not accounted for the regional variations or inadvertent inclusion of blood partial volume in myocardial T1 values,30,31,36 may reveal different results than in the studies using conservative septal ROI.15,26,37 The discriminatory power of ECV values may also suffer from dependency on two separate measurements. Finally, the association between CVF and ECV by MOLLI found in the present study (r = 0.498) compares favourably to the result using tissue FAXS technology33 (r = 0.493). A further interesting finding is the correlation of T1 indices with T2 mapping. This observation communicates an important influence of transverse relaxation, which appears to be captured within the myocardial T1 mapping, consistent with previous reports highlighting the proneness of MOLLI variants to the T2-related errors.20 The effect of magnetization transfer (MT) in MOLLI variants, may be resulting from acquisition of multiple images after each preparation pulse.3,20,38 The difference in FA between implementation of our MOLLI sequence4,10,12 vs. ShMOLLI5 (50° vs. 35°) explains the greater SNR and possibly also the more pronounced T2 and MT effects for MOLLI. Whereas the development of techniques, which are highly accurate for T1 with minimal contamination by T2 or MT or other effects is important for post-contrast T1 acquisitions (i.e. ‘true T1 mapping’), the advantages of the T2-proneness for native T1 mapping—high precision and diagnostic accuracy, yielding higher sensitivity to myocardial pathophysiology, can from the clinical standpoint not be overlooked. Clearly, further research is warranted to elucidate these clinically relevant effects. Lastly, we reveal for the first time that in AS, myocardial native T2 is significantly raised. As it is not significantly associated with myocardial collagen content, it may suggest myocardial oedema.39–42 A body of evidence substantiates the role of inflammatory cellular and extracellular processes in myocardial plasticity and remodelling in response to increased LV wall stress,43,44 including a reactivation of hypertrophic foetal gene programme with phenotypical expression of natriuretic peptides, such as NT-pro BNP, which was also found elevated in the present study.44–47 Increased hs-troponin and CRP levels and relationship with T1 and T2 indices in AS patients may lend a further support to the notion that myocardial oedema, alongside interstitial fibrosis,48 represents a detectable process in extracellular matrix remodelling in hypertrophic cardiac conditions. Study limitations A few limitations apply. This is a single centre, single-vendor and single field-strength comparison study in a sample size, which is based on the previous studies using the identical MOLLI sequence.12 EMBs were performed within the conservative constraints of ethical approval for an invasive procedure performed purely for research purposes. We strived to include a sufficient number of patients required to achieve a significant correlation for native T1 with MOLLI sequence (type I error; α < 0.05) (Type II error; β = 0.8; n = 8), which was also reconfirmed by a posthoc analysis. However, the sample size was not powered to inform on the superiority of correlations between the mapping techniques. The study-design, i.e. head-to-head comparison, and standardized approach to imaging and histology obtained within the same subject, eliminates several important methodological biases, which make comparisons between studies using single techniques difficult. We believe that our results provide a useful guide to the type of much needed evidence, required to support an informed clinical use of T1 mapping sequences. Conclusions We demonstrate that T1 mapping indices and sequences differ in their bioequivalence for detection of abnormal myocardium, which is characterized by diffuse interstitial myocardial fibrosis. Native T1 with MOLLI sequences provides the strongest discriminatory accuracy in characterization of human myocardium. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgments We would like to acknowledge the support of Cardiology and Cardiothoracic Surgery departments at Guy’s and St Thomas’ and King’s College Hospitals NHST Trusts; cardiac radiographers for obtaining the high-quality imaging studies; Philips Clinical Scientists for support: David M. Higgins, PhD; Bernhard Schnackenburg, PhD; Christian Stehning, PhD; Eltjo Haselhoff, PhD. Funding Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. Histological comparisons in aortic stenosis patients were supported by Medical Research Council - Confidence in Concept 2012’ administered through King’s Health Partners project grant (MRJBACR). N.C. was funded by an educational grant from St. Jude Medical. VP, EN, SD, MR-M are supported by the German Centre of Cardiovascular Research (DZHK). Conflict of interest: None declared. References 1 Puntmann VO, Peker E, Chandrashekhar Y, Nagel E. T1 mapping in characterizing myocardial disease. Circ Res  2016; 119: 277– 99. Google Scholar CrossRef Search ADS PubMed  2 Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Dec 11, 2017

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