High-sensitivity troponin I concentrations are a marker of an advanced hypertrophic response and adverse outcomes in patients with aortic stenosis

Aims: High-sensitivity cardiac troponin I (cTnI) assays hold promise in detecting the transition from hypertrophy to heart failure in aortic stenosis. We sought to investigate the mechanism for troponin release in patients with aortic stenosis and whether plasma cTnI concentrations are associated with long-term outcome. Methods and results: Plasma cTnI concentrations were measured in two patient cohorts using a high-sensitivity assay. First, in the Mechanism Cohort, 122 patients with aortic stenosis (median age 71, 67% male, aortic valve area 1.0 ± 0.4 cm2) underwent cardiovascular magnetic resonance and echocardiography to assess left ventricular (LV) myocardial mass, function, and fibrosis. The indexed LV mass and measures of replacement fibrosis (late gadolinium enhancement) were associated with cTnI concentrations independent of age, sex, coronary artery disease, aortic stenosis severity, and diastolic function. In the separate Outcome Cohort, 131 patients originally recruited into the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact of REgression (SALTIRE) study, had long-term follow-up for the occurrence of aortic valve replacement (AVR) and cardiovascular deaths. Over a median follow-up of 10.6 years (1178 patient-years), 24 patients died from a cardiovascular cause and 60 patients had an AVR. Plasma cTnI concentrations were associated with AVR or cardiovascular death HR 1.77 (95% CI, 1.22 to 2.55) independent of age, sex, systolic ejection fraction, and aortic stenosis severity. Conclusions: In patients with aortic stenosis, plasma cTnI concentration is associated with advanced hypertrophy and replacement myocardial fibrosis as well as AVR or cardiovascular death

Towards accurate and precise T1 and extracellular volume mapping in the myocardium: a guide to current pitfalls and their solutions

Mapping of the longitudinal relaxation time (T1) and extracellular volume (ECV) offers a means of identifying pathological changes in myocardial tissue, including diffuse changes that may be invisible to existing T1-weighted methods. This technique has recently shown strong clinical utility for pathologies such as Anderson- Fabry disease and amyloidosis and has generated clinical interest as a possible means of detecting small changes in diffuse fibrosis; however, scatter in T1 and ECV estimates offers challenges for detecting these changes, and bias limits comparisons between sites and vendors. There are several technical and physiological pitfalls that influence the accuracy (bias) and precision (repeatability) of T1 and ECV mapping methods. The goal of this review is to describe the most significant of these, and detail current solutions, in order to aid scientists and clinicians to maximise the utility of T1 mapping in their clinical or research setting. A detailed summary of technical and physiological factors, issues relating to contrast agents, and specific disease-related issues is provided, along with some considerations on the future directions of the field. Towards accurate and precise T1 and extracellular volume mapping in the myocardium: a guide to current pitfalls and their solutions. Available from: https://www.researchgate.net/publication/317548806_Towards_accurate_and_precise_T1_and_extracellular_volume_mapping_in_the_myocardium_a_guide_to_current_pitfalls_and_their_solutions [accessed Jun 13, 2017]

Cardiac T1 Mapping and Extracellular Volume (ECV) in clinical practice: a comprehensive review.

Cardiovascular Magnetic Resonance is increasingly used to differentiate the aetiology of cardiomyopathies. Late Gadolinium Enhancement (LGE) is the reference standard for non-invasive imaging of myocardial scar and focal fibrosis and is valuable in the differential diagnosis of ischaemic versus non-ischaemic cardiomyopathy. Diffuse fibrosis may go undetected on LGE imaging. Tissue characterisation with parametric mapping methods has the potential to detect and quantify both focal and diffuse alterations in myocardial structure not assessable by LGE. Native and post-contrast T1 mapping in particular has shown promise as a novel biomarker to support diagnostic, therapeutic and prognostic decision making in ischaemic and non-ischaemic cardiomyopathies as well as in patients with acute chest pain syndromes. Furthermore, changes in the myocardium over time may be assessed longitudinally with this non-invasive tissue characterisation method

T1 at 1.5T and 3T compared with conventional T2* at 1.5T for cardiac siderosis

Background: Myocardial black blood (BB) T2* relaxometry at 1.5T provides robust, reproducible and calibrated non-invasive assessment of cardiac iron burden. In vitro data has shown that like T2*, novel native Modified Look-Locker Inversion recovery (MOLLI) T1 shortens with increasing tissue iron. The relative merits of T1 and T2* are largely unexplored. We compared the established 1.5T BB T2* technique against native T1 values at 1.5T and 3T in iron overload patients and in normal volunteers. Methods: A total of 73 subjects (42 male) were recruited, comprising 20 healthy volunteers (controls) and 53 patients (thalassemia major 22, sickle cell disease 9, hereditary hemochromatosis 9, other iron overload conditions 13). Single mid-ventricular short axis slices were acquired for BB T2* at 1.5T and MOLLI T1 quantification at 1.5T and 3T. Results: In healthy volunteers, median T1 was 1014 ms (full range 939–1059 ms) at 1.5T and modestly increased to 1165ms (full range 1056–1224 ms) at 3T. All patients with significant cardiac iron overload (1.5T T2* values <20 ms) had T1 values <939 ms at 1.5T, and <1056 ms at 3T. Associations between T2* and T1 were found to be moderate with y =377 · x0.282 at 1.5T (R2 = 0.717), and y =406 · x0.294 at 3T (R2 = 0.715). Measures of reproducibility of T1 appeared superior to T2*. Conclusions: T1 mapping at 1.5T and at 3T can identify individuals with significant iron loading as defined by the current gold standard T2* at 1.5T. However, there is significant scatter between results which may reflect measurement error, but it is also possible that T1 interacts with T2*, or is differentially sensitive to aspects of iron chemistry or other biology. Hurdles to clinical implementation of T1 include the lack of calibration against human myocardial iron concentration, no demonstrated relation to cardiac outcomes, and variation in absolute T1 values between scanners, which makes inter-centre comparisons difficult. The relative merits of T1 at 3T versus T2* at 3T require further consideration

Magnetic resonance imaging phantoms for quality-control of myocardial T1 and ECV mapping: specific formulation, long-term stability and variation with heart rate and temperature

Background: Magnetic resonance imaging (MRI) phantoms are routinely used for quality assurance in MRI centres; however their long term stability for verification of myocardial T1/ extracellular volume fraction (ECV) mapping has never been investigated. Methods: Nickel-chloride agarose gel phantoms were formulated in a reproducible laboratory procedure to mimic blood and myocardial T1 and T2 values, native and late after Gadolinium administration as used in T1/ECV mapping. The phantoms were imaged weekly with an 11 heart beat MOLLI sequence for T1 and long TR spin-echo sequences for T2, in a carefully controlled reproducible manner for 12 months. Results: There were only small relative changes seen in all the native and post gadolinium T1 values (up to 9.0 % maximal relative change in T1 values) or phantom ECV (up to 8.3 % maximal relative change of ECV, up to 2.2 % maximal absolute change in ECV) during this period. All native and post gadolinium T2 values remained stable over time with <2 % change. Temperature sensitivity testing showed MOLLI T1 values in the long T1 phantoms increasing by 23.9 ms per degree increase and short T1 phantoms increasing by 0.3 ms per degree increase. There was a small absolute increase in ECV of 0.069 % (~0.22 % relative increase in ECV) per degree increase. Variation in heart rate testing showed a 0.13 % absolute increase in ECV (~0.45 % relative increase in ECV) per 10 heart rate increase. Conclusions: These are the first phantoms reported in the literature modeling T1 and T2 values for blood and myocardium specifically for the T1mapping/ECV mapping application, with stability tested rigorously over a 12 month period. This work has significant implications for the utility of such phantoms in improving the accuracy of serial scans for myocardial tissue characterisation by T1 mapping methods and in multicentre work

Identification of myocardial diffuse fibrosis by 11 heartbeat MOLLI T1 mapping: averaging to improve precision and correlation with collagen volume fraction

Objectives: Our objectives involved identifying whether repeated averaging in basal and mid left ventricular myocardial levels improves precision and correlation with collagen volume fraction for 11 heartbeat MOLLI T1 mapping versus assessment at a single ventricular level. Materials and methods: For assessment of T1 mapping precision, a cohort of 15 healthy volunteers underwent two CMR scans on separate days using an 11 heartbeat MOLLI with a 5(3)3 beat scheme to measure native T1 and a 4(1)3(1)2 beat post-contrast scheme to measure post-contrast T1, allowing calculation of partition coefficient and ECV. To assess correlation of T1 mapping with collagen volume fraction, a separate cohort of ten aortic stenosis patients scheduled to undergo surgery underwent one CMR scan with this 11 heartbeat MOLLI scheme, followed by intraoperative tru-cut myocardial biopsy. Six models of myocardial diffuse fibrosis assessment were established with incremental inclusion of imaging by averaging of the basal and mid-myocardial left ventricular levels, and each model was assessed for precision and correlation with collagen volume fraction. Results: A model using 11 heart beat MOLLI imaging of two basal and two mid ventricular level averaged T1 maps provided improved precision (Intraclass correlation 0.93 vs 0.84) and correlation with histology (R2 = 0.83 vs 0.36) for diffuse fibrosis compared to a single mid-ventricular level alone. ECV was more precise and correlated better than native T1 mapping. Conclusion: T1 mapping sequences with repeated averaging could be considered for applications of 11 heartbeat MOLLI, especially when small changes in native T1/ECV might affect clinical management

Calibration of myocardial T2 and T1 against iron concentration.

BACKGROUND: The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron. METHODS: Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n=7) or cardiac transplantation (n=4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1=1/T1 and R2=1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy. RESULTS: From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (± SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p<0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R2 0.566, p<0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R2 0.790, p<0.001). The relation was [Fe] = 5081•(T2)-2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R2 0.517, p<0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R2 0.657, p<0.001). CONCLUSION: Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies

Prospective, randomized comparison of gadopentetate and gadobutrol to assess chronic myocardial infarction applying cardiovascular magnetic resonance

BACKGROUND: We hypothesized that the contrast medium gadobutrol is not inferior compared to Gd-DTPA in identifying and quantifying ischemic late gadolinium enhancement (LGE), even by using a lower dose. METHODS: We prospectively enrolled 30 patients with chronic myocardial infarction as visualized by LGE during clinical routine scan at 1.5 T with 0.20 mmol/kg Gd-DTPA. Participants were randomized to either 0.15 mmol/kg gadobutrol (group A) or 0.10 mmol/kg gadobutrol (group B). CMR protocol was identical in both exams. LGE was quantified using a semiautomatic approach. Signal intensities of scar, remote myocardium, blood and air were measured. Signal to noise (SNR) and contrast to noise ratios (CNR) were calculated. RESULTS: Signal intensities were not different between Gd-DTPA and gadobutrol in group A, whereas significant differences were detected in group B. SNR of injured myocardium (53.5+/-21.4 vs. 30.1+/-10.4, p = 0.0001) and CNR between injured and remote myocardium (50.3+/-20.3 vs. 27.3+/-9.3, p < 0.0001) were lower in gadobutrol. Infarct size was lower in both gadobutrol groups compared to Gd-DTPA (group A: 16.8+/-10.2 g vs. 12.8+/-6.8 g, p = 0.03; group B: 18.6+/-12.0 g vs. 14.0+/-9.9 g, p = 0.0016). CONCLUSIONS: Taking application of 0.2 mmol/kg Gd-DTPA as the reference, the delineation of infarct scar was similar with 0.15 mmol/kg gadobutrol, whereas the use 0.10 mmol/kg gadobutrol led to reduced tissue contrast. TRIAL REGISTRATION: The study had been registered under EudraCT Number: 2010-020775-22 . Registration date: 2010.08.10

A medical device-grade T1 and ECV phantom for global T1 mapping quality assurance - the T1_1 Mapping and ECV Standardization in cardiovascular magnetic resonance (T1MES) program

$\textbf{Background:}$ T$_1$ mapping and extracellular volume (ECV) have the potential to guide patient care and serve as surrogate end-points in clinical trials, but measurements differ between cardiovascular magnetic resonance (CMR) scanners and pulse sequences. To help deliver T$_1$ mapping to global clinical care, we developed a phantom-based quality assurance (QA) system for verification of measurement stability over time at individual sites, with further aims of generalization of results across sites, vendor systems, software versions and imaging sequences. We thus created T1MES: The T1 Mapping and ECV Standardization Program. $\textbf{Methods:}$ A design collaboration consisting of a specialist MRI small-medium enterprise, clinicians, physicists and national metrology institutes was formed. A phantom was designed covering clinically relevant ranges of T$_1$ and T$_2$ in blood and myocardium, pre and post-contrast, for 1.5 T and 3 T. Reproducible mass manufacture was established. The device received regulatory clearance by the Food and Drug Administration (FDA) and Conformité Européene (CE) marking. $\textbf{Results:}$ The T1MES phantom is an agarose gel-based phantom using nickel chloride as the paramagnetic relaxation modifier. It was reproducibly specified and mass-produced with a rigorously repeatable process. Each phantom contains nine differently-doped agarose gel tubes embedded in a gel/beads matrix. Phantoms were free of air bubbles and susceptibility artifacts at both field strengths and T$_1$ maps were free from off-resonance artifacts. The incorporation of high-density polyethylene beads in the main gel fill was effective at flattening the $B_1$ field. T$_1$ and T$_2$ values measured in T1MES showed coefficients of variation of 1 % or less between repeat scans indicating good short-term reproducibility. Temperature dependency experiments confirmed that over the range 15-30 °C the short-T$_1$ tubes were more stable with temperature than the long-T$_1$ tubes. A batch of 69 phantoms was mass-produced with random sampling of ten of these showing coefficients of variations for T$_1$ of 0.64 ± 0.45 % and 0.49 ± 0.34 % at 1.5 T and 3 T respectively. $\textbf{Conclusion:}$ The T1MES program has developed a T$_1$ mapping phantom to CE/FDA manufacturing standards. An initial 69 phantoms with a multi-vendor user manual are now being scanned fortnightly in centers worldwide. Future results will explore T$_1$ mapping sequences, platform performance, stability and the potential for standardization.This project has been funded by a European Association of Cardiovascular Imaging (EACVI part of the ESC) Imaging Research Grant, a UK National Institute of Health Research (NIHR) Biomedical Research Center (BRC) Cardiometabolic Research Grant at University College London (UCL, #BRC/ 199/JM/101320), and a Barts Charity Research Grant (#1107/2356/MRC0140). G.C. is supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC) and by the NIHR UCL Hospitals Biomedical Research Center. J.C.M. is directly and indirectly supported by the UCL Hospitals NIHR BRC and Biomedical Research Unit at Barts Hospital respectively. This work was in part supported by an NIHR BRC award to Cambridge University Hospitals NHS Foundation Trust and NIHR Cardiovascular Biomedical Research Unit support at Royal Brompton Hospital London UK