Cardiac Magnetic Resonance T1 Mapping in Cardiomyopathies Cardiac Magnetic Resonance T1 Mapping in Cardiomyopathies

Cardiac magnetic resonance (CMR) imaging has been widely used to assess myocardial perfusion and scar and is the noninvasive reference standard for identification of focal myocardial fibrosis. However, the late gadolinium enhancement (LGE) technique is limited in its accuracy for absolute quantification and assessment of diffuse myocardial fibrosis by technical and pathophysiological features. CMR relaxometry, incorporating T1 mapping, has emerged as an accurate, reproducible, highly sensitive, and quantita‐ tive technique for the assessment of diffuse myocardial fibrosis in a number of disease states. We comprehensively review the physics behind CMR relaxometry, the evidence base, and the clinical applications of this emerging technique.


Introduction
Cardiac Magnetic Resonance (CMR) imaging has been used widely to assess myocardial perfusion and scar [1][2][3][4][5]. It is the noninvasive reference standard for left and right ventricular quantitation, as well as the assessment and quantitation of focal myocardial fibrosis (after infarction or due to other causes of cellular injury). Myocardial necrosis causes high signal on late gadolinium enhancement (LGE) inversion recovery T1-weighted images with excellent signal-noise ratios, and this has become the reference standard for noninvasive scar imaging in cardiomyopathies of various causes [1][2][3][4]. However, LGE is limited in its ability to assess and quantitate diffuse (nonfocal) myocardial injury and fibrosis. LGE is affected by inconsistencies in acquisition parameters, such as choice inversion time, and in postprocessing when signal intensity thresholds may be arbitrarily applied to distinguish normal myocardium from fibrotic tissue [6,7]. Moreover, the critical issue with LGE is that signal intensity is expressed on an arbitrary scale (relative signal intensity compared with "nulled" normal myocardium). Detection of myocardial fibrosis using relative differences between scar and normal myocardium tissue is therefore qualitative. Thus, in nonischemic cardiomyopathies, such as hypertension or diabetes, LGE CMR is unable to detect signal differential where the collagen deposition is diffuse and widespread throughout the myocardium [8].

CMR relaxometry
CMR is an evolving technique, providing valuable and comprehensive data on the anatomy and functional integrity of both the heart and coronary blood vessels. Currently, CMR is performed at magnetic field strengths of 1.5 or 3 T.

T1 mapping with Look-Locker
The initial technique to measure spin-lattice T1 relaxation time values was the eponymously named "Look-Locker" sequence (also known as "TI scout"). It has been widely used to estimate the optimal inversion time for assessment of myocardial LGE [9,10]. It was originally proposed by Look and Locker in 1968 and analyzed more fully in 1970 [11] and consists of an initial inversion pulse, followed by a train of pulses with a constant, limited flip angle (7-15°).
The development of LL technique is summarized in Table 1.
The LL sequence has been widely applied in CMR due to its fast acquisition with minimal breath-hold requirements. The LL sequence has been used to measure T1 values in patients with myocardial fibrosis [9]. However, it suffers from significant limitations: low flip angle RF pulse exciting the magnetization and the two RR intervals in the LL sequence are not sufficient for the magnetization to return to equilibrium. This causes underestimation of true T1 values using LL. Furthermore, the LL T1 images with different TIs are acquired at different cardiac phases. Therefore, images are "cine" with cardiac motion effect, which requires tedious manual tracking of the myocardial borders for each phase, a labour-intensive and error-prone process, which is challenging in clinical practice. The drawing of regions of interest "ROI" in myocardial segments requires adjusting for cardiac motion, which results in including blood pool (partial volume averaging) and artificially increasing the measured T1 [12].
To address these shortcomings, several myocardial T1 mapping sequences have been created, including modified Look-Locker inversion (MOLLI) recovery.
MOLLI is a CMR pulse sequence that is used for accurate T1 mapping of myocardium with high spatial resolution. MOLLI is an ECG-gated pulse sequence scheme and uses three prepared Look-Locker experiments consecutively within one breath-hold over 17 heartbeats to reconstruct 11 images with different inversion times. Three successive ECG-triggered LL experiments (LL1, LL2, and LL3) are carried out with three, three, and five single-shot readouts, respectively, at end diastole of consecutive heartbeats to sample the recovery of longitudinal magnetization after the inversion pulse. MOLLI pulse sequence scheme is illustrated in Figure 1. T1 maps can be generated any time before or after contrast agent (e.g., gadolinium) administration [12]. The MOLLI sequence has been described, optimized, tested, and retested in phantoms and in large cohorts of healthy volunteers [12,14] as well as being applied in cardiomyopathies [8,15,17,19,20]. In addition, the T1 mapping with MOLLI has been validated against histopathology for assessment of myocardial fibrosis. It demonstrated that the precontrast "native T1" has a linear correlation with the percentage of myocardial fibrosis as measured histologically on invasive myocardial biopsy. T1 times postcontrast administration (10-15 min) had an inverse linear relationship with collagen content in myocardial fibrosis subjects [8,21,22].
• Precontrast "Native" T1 = predominant signal from myocytes (replacement fibrosis or intracellular accumulation, e.g., Fabry disease) • Postcontrast T1 = predominant signal from interstitial space (interstitial fibrosis) T1 mapping can be generated for different segments of the myocardium (base, mid-cavity, and apex) within a single breath-hold of about 15-20 s. However, the apex T1 values with MOLLI are slightly higher than basal and mid-cavity. The increasing in T1 values may be caused by partial volume effect and some degree of overestimation effect in apical level of left ventricle [23][24][25].
T1 mapping with MOLLI has a greater reproducibility, accuracy, and an excellent overall interand intra-observer agreement over a wide range of TIs as compared with the traditional LL sequence [13,14].
However, the T1 mapping with MOLLI sequence is sensitive to extremes of heart rate (bradycardia or tachycardia) [14] leading to a slight underestimation of T1 values. This may be corrected though heart rate correction by changing the timing of the readouts with respect to the inversion pulses at different heart rates.
Moreover, MOLLI is also limited by long breath-hold for about 15-20 s (17 heartbeats to acquire the final T1 maps). This may be difficult for elderly and pulmonary compromised patients and generates respiratory and motion artifacts [26]. Modern in-line processing provides registration tools to reduce motion artifacts before the computation of final T1 maps (motion-corrected or "MoCo MOLLI") [27]. A shortened Modified Look-Locker inversion recovery (shMOLLI) with shorter breath-holds has been validated and recently applied for cardiomyopathies [28,29].
3 T: T1 mapping at higher magnetic field (3 T) has been reported in a few studies of interstitial myocardial fibrosis, but minimal data exist for ultra-high field at 7 T. 3 T data are similar to 1.5 T, the precontrast T1 was longer, and postcontrast T1 was shorter in myocardial fibrosis patients compared with normal myocardium. Puntmann et al. [30] reported higher precontrast T1 values for hypertrophic and nonischemic dilated cardiomyopathies at 3 T compared with controls (Hypertrophic 1.254 ± 43 ms, and nonischemic dilated cardiomyopathy 1.239 ± 57 ms vs. healthy 1.070 ± 55 ms). Also, the postcontrast T1 values (10 mins) at 3 T were shorter in hypertrophic and dilated cardiomyopathies compared with healthy (hypertrophic: 307 ± 47 ms, dilated cardiomyopathies: 296 ± 43 ms vs. controls: 402 ± 58 ms) [30].
There are studies published for normal and diffuse myocardial fibrosis of myocardium T1 values, as described comprehensively in Tables 2 and 3:

Limitations of T1 mapping
Challenges remain with myocardial relaxometry for T1 mapping. These include technical challenges such as variations of T1 times at different field strength and across different vendors, and the rapidity in growth of pulse sequences being released as product and as works-inprogress (WIP), calling into question both the inherent accuracy and the level agreement between these techniques. Furthermore, the variations in T1 relaxometry values with different contrast doses and image timing require further investigation to establish the test-retest and intersite reproducibility of this technique. Next, the challenges to application of T1 mapping to clinical practice include establishment of robust normal ranges in large cohorts across multiple ethnic groups and the observation that T1 mapping appears to be a highly sensitive technique, with the ability to discriminate healthy normal myocardium and identify very early changes in substrate. However, this technique lacks specificity; a wide variety of conditions prolong native T1 and/or shorten postcontrast myocardial T1. Therefore, further clinical data are required in order to establish the use of these parameters in relation to disease (e.g., early detection of target organ damage in systemic conditions such as hypertension or diabetes), to inform treatment decisions, and their ability to predict or alter clinical outcomes.

Conclusions
Myocardial T1 mapping using quantitative relaxometry is an emerging and important tool in the assessment of global myocardial fibrosis. It is a highly sensitive marker of disease, but is not specific, with changes in myocardial T1 occurring in many different conditions. Nevertheless, the high sensitivity and excellent reproducibility of the technique offer a tool for the early detection of myocardial damage, over-and-above techniques such as the CMR LGE technique and other modalities such as speckle tracking echocardiography, pulse wave velocity, and tissue tagging. Native T1 mapping is proving to be a robust indicator of early myocardial disease in many conditions, and normal ranges and guidelines for postprocessing have been published by the Society of Cardiovascular Magnetic Resonance [41]. Myocardial T1 mapping is a rapidly evolving technique, now with longitudinal prognostic data emerging, and normal ranges established at 1.5 and 3.0 T in healthy humans and in aging persons. Further questions remain as to the standardization of pulse sequences across field strengths and between vendors, the affect of contrast type, dose and timing, the postprocessing software, and the interpretation of T1 mapping results to inform clinical practice.

Acknowledgements
The author acknowledges the contribution of Dr Qurain Alshammari's to the background work.