T1 and T2 Mapping and Extracellular Volume in Cardiomyopathy

Cardiovascular magnetic resonance (CMR) exploits the inherent difference between tissues in their configuration of atoms by generating differing signals—the fundamental tissue properties T1, T2, and T2*. Whereas differences in these parameters had to be previously visualized by weighted sequences, they can now be measured in a single breath-hold with T1, T2, or T2* displayed as pixel maps where each color-coded pixel carries the absolute value. Furthermore, if T1 is measured before and after contrast, the myocardial extracellular volume (ECV) is mapped, representing the percentage of tissue that is extracellular water, a surrogate for the process holding water, be it fibrosis, amyloid, or edema. In turn, T2 mapping is a highly attractive technique for characterization of myocardial tissue in the disease state accompanied by inflammation. T1, T2, and ECV change in disease, each being differentially sensitive to pathologic processes ( Fig. 32.1 ). The technique potential is best considered in rare (infiltrations), common (edema), and ubiquitous (diffuse fibrosis) disease processes.

Tissue Characterization: Moving Beyond Late Gadolinium Enhancement

The key single technique that stimulated the greater adoption of CMR into routine clinical practice was scar imaging. The late gadolinium enhancement (LGE) technique was first used in infarction, but it has proved to be reproducible and robust enough for use in a multicenter clinical trial, and it has established itself as the gold standard method in both ischemic and nonischemic heart diseases, including cardiomyopathy, myocarditis, aortic stenosis-induced pressure-overload hypertrophy, and infiltrative diseases. However, LGE is a difference test between normal and abnormal myocardium, and therefore is not able to characterize and quantify diffuse myocardial disease or inform on how nonscarred areas are adapting to the increased workload or whether they are at risk of generating new scar. There are many pathways active in normal myocardium, and these change with different pathologic processes. Each parameter may be differently sensitive to these. Multiparametric tissue characterization is therefore an attractive strategy for noninvasive “biopsy” and “whole heart” sampling, avoiding potential morbidity and mortality of actual biopsy.

Histologic Validation of T1, T2, and Extracellular Volume

Extracellular tracers for measuring the interstitium were first described in the 1960s. In the 1970s, Poole-Wilson et al. used ⁵¹ Cr-EDTA in an ex vivo heart model with photographic paper to measure the myocardial extracellular volume. Early in vitro work by Kehr et al. on human myocardium obtained postmortem compared T1 values, calculated from the inversion recovery signal curves, with collagen volume fraction, determined by the picrosirius red method, and showed a significant correlation between the two methods. In 2010, Flett et al. developed an at equilibrium extracellular volume technique and validated it in patients with severe aortic stenosis and hypertrophic cardiomyopathy (HCM). The ECV showed a high correlation with the collagen volume fraction of biopsies obtained intraoperatively in this cohort. This work has been replicated in transplant hearts, shorter protocols, and with newer, faster T1 mapping sequences ( Tables 32.1 and 32.2 ).

TABLE 32.1

Histologic Validation Cohorts in T1 and T2 Mapping

Reference	Year	Population	N	Parameter	Sequence
Iles et al.	2008	DCM	25	Postcontrast T1	1.5 T; IR VAST
Flett et al.	2010	AS/HCM	26	ECV	1.5 T; EQ-CMR; multibreath-hold FLASH IR
Sibley et al.	2012	DCM/IHD/HCM/amyloid	47	Postcontrast T1	1.5 T, IR Look-Locker
Mascherbauer et al.	2013	HFpEF	9	Postcontrast T1	1.5 T, IR FLASH
White et al.	2013	AS	18	ECV	1.5 T; EQ-CMR; ShMOLLI
Miller et al.	2013	DCM/IHD (transplant)	6	ECV	1.5 T, MOLLI
Bull et al.	2013	AS	19	Native T1	1.5 T; ShMOLLI
Lee et al.	2015	AS	20	Native T1	3 T, MOLLI
De Meester et al.	2015	AS/AR/MR	31	T1 and ECV	3 T, MOLLI
Kammerlander et al.	2016	Mixed HF	36	ECV	1.5 T, MOLLI
Lurz et al.	2016	Myocarditis	129	T1/T2/ECV	1.5 T and 3 T, MOLLI

AR, Aortic regurgitation; AS, aortic stenosis; CMR , cardiovascular magnetic resonance ; DCM, dilated cardiomyopathy; ECV , extracellular volume fraction; EQ, equilibrium contrast; HCM , hypertrophic cardiomyopathy; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; IHD, ischemic heart disease; IR, inversion recovery; MOLLI, modified Look-Locker inversion recovery; MR, mitral regurgitation; ShMOLLI, shortened modified Look-Locker inversion.

TABLE 32.2

Overview of T1, T2, and Extracellular Volume Fraction Mapping in Myocardial Disease ^a

Modified from Captur G, Manisty C, Moon JC. Cardiac MRI evaluation of myocardial disease. Heart. 2016;102(18):1429--1435.

^b If myocardial hemorrhage accompanies acute infarction.

^c In acute heart failure.

ECV, Extracellular volume; —, no significant change; ↑, significant increase; ↓, significant decrease;

, unreported to date.

a Reference list is nonexhaustive—several other references may exist that are not listed here.

Native T1, Postcontrast T1, and Extracellular Volume

Native T1

Native T1 measures the intrinsic signal from the combined cellular and interstitial compartments of the myocardium. The advantages are that it does not require an exogenous gadolinium-based contrast agent. Native T1 relaxation time is prolonged with collagen (fibrosis), edema, and amyloid and is shortened with reduced fibrosis, iron, fat, and hemorrhage. Given that native T1 measures both interstitium and myocyte T1, a signal from the interstitium alone is somewhat diluted by the myocyte signal, so subtle differences (diffuse fibrosis) are harder to detect. Moreover, capillary density, capillary vasodilatation, and “partial voluming” between blood pool and myocardium are also measured, potential biases if the signal sought is the matrix or myocyte compartments alone. Native T1 time is different with field strength and sequence design and varies between scanners, making comparison of native and postcontrast values between centers challenging. Currently, several groups have developed T1 phantoms to facilitate multicenter trials (Hypertrophic CardioMyopathy Registry [HCMR] ) or develop reference standards (T1 mapping and ECV standardization in CMR [T1MES] program ).

Postcontrast T1

After administration of gadolinium, T1 is dominated by, and inversely proportional to, the concentration of tissue gadolinium. Measuring T1 after contrast provides a value linked to the interstitium and has been applied to patients with heart failure. Postcontrast T1 also varies with gadolinium dose, time post bolus, and importantly, patient-specific factors such as heart rate, clearance rate, body composition, and hematocrit.

Extracellular Volume Fraction

If the change in T1 precontrast and postcontrast is measured in both blood and myocardium after sufficient equilibration of the contrast distribution, the partition coefficient can be calculated. By adding in the blood compartment contrast volume of distribution (1 − hematocrit), the myocardial ECV is derived ( Fig. 32.2 ). ECV is a more stable and biologically significant biomarker, as well as a more robust parameter than T1.

FIG. 32.2, Native T1, postcontrast T1, and extracellular volume (ECV). ECV maps derived by acquiring hematocrit (HCT) , native T1, and postcontrast T1 modified Look-Locker inversion recovery of the short axis of a healthy volunteer.

Extracellular Volume Fraction Dichotomizing the Myocardium Into Cell and Matrix Components

ECV divides the myocardium into two compartments (extracellular and cellular) and, therefore allows noninvasive quantification of the myocardial matrix volume and its counter-part, cell volume ( Fig. 32.3 ). The cell volume represents intact myocardial cellular components, proving a way to measure the myocyte volume (note that this also includes fibroblasts, blood cells, macrophages, etc.). How these change in disease (e.g., left ventricular hypertrophy [LVH]) is important. For example, in transthyretin-related (TTR) hereditary amyloidosis and light-chain amyloidosis, both have a massive matrix increase, but TTR has more matrix and 20% higher cell volume suggesting compensatory hypertrophy, which may permit more tolerance of the amyloid burden. By modeling water exchange, there is also some evidence that the contrast kinetics could be used to obtain cell size-dependent parameters, particularly if very high doses of gadolinium contrast are used.

$FIG. 32.3, Extracellular volume (ECV) divides the myocardium into cell and matrix components. In diseases with global homogeneous hypertrophy and extracellular matrix expansion, the ECV fraction may offer limited information, because it just depicts the ratio between cell and matrix volumes. By multiplying the left ventricular mass (LVM) with the global ECV, matrix volume (LVM * ECV) and cell volume (LVM * [1 − ECV]) can be derived, respectively. LVH, Left ventricular hypertrophy.$

T1 Mapping Evolution

The T1 mapping field is rapidly advancing to the point of widespread clinical utility. The first to T1 mapping was Messroghli in 2004 with a pulse-sampling scheme known as MOLLI (modified Look-Locker inversion recovery), replacing previous multibreath-hold approaches. This was refined, including new MOLLI variants, shortened modified Look-Locker inversion recovery (ShMOLLI; a shortened variation with long T1 advantages ), saturation recovery variants such as saturation recovery single-shot acquisition (SASHA; offering complete heart rate insensitivity ) or hybrid approaches (accelerated and navigator-gated Look-Locker imaging for cardiac T1 estimation [ANGIE], quantification using an interleaved Look-Locker acquisition sequence with T2 preparation pulse [QALAS], SAturation Pulse Prepared Heart rate independent Inversion-REcovery sequence [SAPPHIRE] ). Incremental developments such as respiratory motion correction gradually increased accuracy and precision. For ECV, contrast regimes were simplified from bolus followed by infusion or multi-timepoint sampling to a single precontrast and single postcontrast T1 map. Split contrast dose protocols suitable for stress perfusion imaging have been validated. ECV maps are now routine in some centers. ECV quantification is less field and sequence sensitive than native T1 mapping but ECV standardization is ongoing. Most recently, it was a found that a synthetic ECV can be automatically generated during scanning, in which the hematocrit of blood is inferred from the T1 of the blood pool (as the relationship between hematocrit and R1 [1/Blood T1] is linear), removing the need for a blood test. Finally, magnetic resonance fingerprinting may offer more rapid multiparametric tissue characterization in the future by providing myocardial T1, T2, and proton spin density in a single breath-hold.

For clinical use, these developments need to transition to standardized methodologies to diagnose disease; define mechanistic pathways of disease affecting the interstitium, the myocyte, or both; change therapy; and employ ECV as a surrogate endpoint in trials of drug development. This is the aim underpinning the first T1 mapping consensus statement. Our conceptual models are simple, but there is more going on; effects such as magnetization transfer, diffusion distance and time, contrast mechanisms, transcytolemmal water exchange rate, flow, T2 or T2* relaxation will require further investigation. Part of this development requires global approaches. Quality control systems, commercial sequences, megaregistries (e.g., Global CMR Registry, HCM Registry, UK Biobank) are in progress, and will provide high volumes of new insights in what is now the most active CMR research area.

Continuous Improvement Versus Stability

For a “feel” for the potential of mapping in different pathologic processes compared with health, transform the absolute difference into the maximum possible signal-to-noise ratio (SNR) in standard deviation (SD) units in severe but not extreme disease (a measure of effect size). Provided minimal systematic bias by disease-tracking confounders, such as heart rate or anemia, an SD change of 2 suggests the technique can detect between-group differences for biologic insights, >4 and it could determine the choice of therapy in individuals, and >6 said therapy could be monitored during treatment. A measured value consists of combined biologic and measurement variability. Considerable ongoing work is reducing the measurement variability, so the above SD changes are increasing with technical development.

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