Heart Fail Rev DOI 10.1007/s10741-014-9470-7
Cardiovascular magnetic resonance for amyloidosis Marianna Fontana • Robin Chung • Philip N. Hawkins • James C. Moon
Ó Springer Science+Business Media New York 2014
Abstract Cardiac involvement drives the prognosis and treatment in systemic amyloid. Echocardiography, the mainstay of current cardiac imaging, defines cardiac structure and function. Echocardiography, in conjunction with clinical phenotype, electrocardiogram and biomarkers (brain natriuretic peptide and troponin), provides an assessment of the likelihood and extent of cardiac involvement. Two tests are transforming our understanding of cardiac amyloidosis, bone tracer scanning and cardiovascular magnetic resonance (CMR). CMR provides a ‘‘second opinion’’ on the heart’s structure and systolic function with better accuracy and more precision than echocardiography but is unable to assess diastolic function and is not as widely available. Where CMR adds unique advantages is in evaluating myocardial tissue characterisation. With administration of contrast, the latest type of late gadolinium enhancement imaging (phase-sensitive inversion recovery sequence) is highly sensitive and specific with images virtually pathognomonic for amyloidosis. CMR is also demonstrating that the range of structural and functional changes in cardiac amyloid is broader than
M. Fontana R. Chung J. C. Moon (&) The Heart Hospital Imaging Centre, 16–18 Westmoreland Street, London W1G 8PH, UK e-mail: [email protected] M. Fontana J. C. Moon Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK M. Fontana P. N. Hawkins National Amyloidosis Centre, Royal Free Hospital, University College London, London, UK
traditionally thought. CMR with T1 mapping, a relatively new CMR technique, can measure the amyloid burden and the myocyte response to infiltration (hypertrophy/cell loss) with advantages for tracking change (e.g. the wall thickness can stay the same but the composition can change) over time or during therapy. Such techniques hold great promise for advancing drug development in this arena and providing new prognostic insights. CMR with tissue characterisation is rewriting our understanding of cardiac amyloidosis and may lead to the development of new classification, therapies and prognostic systems. Keywords
Amyloidosis CMR T1 mapping
Introduction Systemic amyloidosis frequently involves the heart. Cardiac involvement drives prognosis and determines choice and effectiveness of therapy [1]. New treatments are pending that may specifically target cardiac involvement [2]. Whilst there may be amyloid in the degenerating aortic valve (origin: probably Apolipoprotein A1) [3] and in the atria (origin: atrial natriuretic peptide, ANP) [4], ventricular myocardium is primarily affected by immunoglobulin light chain (AL or primary systemic) type and transthyretin (ATTR) type amyloidosis—both wild type and mutant [5]. The traditional view is that cardiac amyloidosis (cardiac amyloid where the amyloid burden is sufficient to cause disease) is a disease of infiltration leading to adverse outcomes. The reality from experimental studies, biomarker analysis and imaging research is that the infiltration may trigger changes in interstitium and myocytes with resulting hypertrophy, myocyte loss and collagen deposition. Given that over half perhaps two-thirds of the heart can be
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amyloid in a living person, amyloid must be either remarkably benign, the myocardium remarkably adaptable or the heart has huge functional reserves. Nevertheless, it is the relentless and possible runaway nature of deposition that is the major problem.
history), clinical examination, ECG, 24-h Holter monitoring, other imaging investigations (echocardiography, bone tracer scanning), blood biomarkers (troponin, brain natriuretic peptides), myocardial biopsy and, importantly, other essential tests (such as free light chains and other organ biopsies including bone marrow) and genotyping.
Cardiac investigations (cardiovascular magnetic resonance in context)
CMR
Detecting and quantifying cardiac amyloid infiltration and the myocardial response are a crucial step in understanding the disease. The gold standard for the diagnosis and subtyping of cardiac amyloidosis is histology (Fig. 1), ideally with specialist analysis (immunofixation/microdissection for proteomics), but cardiac biopsy carries a risk of morbidity and mortality. Furthermore, the patchiness of the cardiac amyloid deposition makes this approach an unreliable method to track serial change over time (Fig. 1). Cardiovascular magnetic resonance (CMR) can measure the structure and function of the heart and uniquely enables whole heart myocardial tissue characterisation. For many important parameters, it is a more reproducible modality, meaning that change (with therapy, with progression or occasionally with regression) is more easily detected. However, CMR, like all other tests, is just one test within the portfolio of history taking (cardiac, multisystem, family
CMR uses a superconducting magnet with ECG gating to investigate the heart, gaining insight into the extracardiac anatomy, cardiac structure, function and specific characterisations of myocardial tissue. CMR may have high sensitivity and specificity, but the diagnostic yield and importance of findings depend on the pre-test probability. Advanced cardiac amyloidosis is easy to detect by any technique: the detection of early cardiac involvement and the distinction from other phenocopies is more difficult. CMR, like other tests, should therefore be interpreted in the clinical context. Specific differentials or disease processes that may raise diagnostic problems and confounders are comorbidities such as age, renal failure, diabetes, hypertension and another cardiomyopathy such as hypertrophic cardiomyopathy (HCM) and the presence of dual pathology—for example aortic stenosis and wild-type ATTR amyloidosis.
Fig. 1 Left panes: examples of the different degrees of amyloid infiltration (in black) with comparable left ventricular wall thickness: a extensive and diffuse infiltration; b subendocardial infiltration
(Adapted from Leone et al. [42]). Right panels: endomyocardial biopsy with immunochemistry of a patient with AL amyloidosis c and a patient with ATTR amyloidosis d
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Traditionally, cardiac amyloidosis has been thought to be characterised by concentric and symmetric hypertrophy of the left ventricle as opposed to apical or asymmetric wall thickening in HCM (Fig. 3). However, recent work
documents concentric left ventricular hypertrophy (LVH) in 59 % of patients with cardiac amyloidosis, eccentric LVH or concentric remodelling in 33 % and normal geometry in the remaining 8 % [6]. Cardiac amyloidosis may present with symmetric or asymmetric, concentric or eccentric hypertrophy (Fig. 3). Hypertrophy may be disproportionately greater than in hypertension (e.g. greater than *17 mm) and is more prominent in ATTR than in AL amyloid. Right ventricular (RV) involvement with hypertrophy is frequent—the RV end systolic thickness may be up to 1 cm. A few cases have been observed with a dilated cardiomyopathy phenotype (again with classical tissue characterisation findings) (Fig. 3), and occasionally, patients have outflow tract obstruction. Thus, although many cases are characteristic, the full range of morphological findings in amyloid is broad. Traditional markers such as ejection fraction may be normal even into the late phase of disease because it is a poor measure of systolic function in patients with concentric remodelling. Long axis function (typically biventricular) declines early, mainly at the level of the basal segments. The reduction, in many cases to effectively zero longitudinal function, is associated with small cavity size, decreased stroke volume and reduced cardiac output [7]. The indexed stroke volume, usually severely reduced, is therefore a better measure of systolic function than the ejection fraction, and we would recommend scrutinising it in reports of possible cardiac amyloid.
Fig. 2 Examples of frequent extracardiac findings in patients with cardiac amyloidosis. a Pleural and pericardial effusions. b Ascites without pleural effusions. c Right pleural effusion. d Lardaceous fatty
liver with its featureless hypovascular appearance. e Tortuous and dilated thoracic aorta, frequently seen in hypertension, one of the main differentials. f Patchy lung changes (non-specific by CMR)
CMR findings in amyloidosis Extracardiac anatomy Cardiac amyloidosis is frequently associated with other abnormalities. Pleural effusions are common, as is ascites in advanced disease (Fig. 2). The presence of effusions and ascites when there is preserved systolic function (e.g. a normal ejection fraction) is one clue to the presence of cardiac amyloidosis. Additionally, the presence of ascites, indicative of right heart failure, is often observed in the later phases of cardiac amyloidosis (Fig. 2). Patchy lung changes are not infrequently seen, but many patients are elderly, and CMR is not adequate to diagnose lung infiltration (Fig. 2). Occasionally, the presence of increased gas in the bowel or dilated oesophagus from autonomic dysfunction can be seen. Similarly, liver changes are occasionally seen—fatty liver with its featureless hypovascular appearance is an occasional finding in patients with known AL amyloidosis (Fig. 2). Morphology, function and anatomy
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Fig. 3 Left ventricular remodelling phenotypes in cardiac amyloidosis. For each pattern, there is an example of a cine four chamber view and a short axis late gadolinium enhancement. Left upper panel: symmetric hypertrophy, traditionally considered the characteristic pattern. Right upper panel: asymmetric hypertrophy, recently proven
to be highly prevalent in cardiac amyloidosis. Left lower panel: dilated cardiomyopathy phenotype (rarely described in few cases). Right lower panel: no left ventricular hypertrophy with late gad features of amyloidosis, a less uncommon finding that is hard to detect without tissue characterisation
CMR is less adept than echocardiography for diastolic function assessment. Valvular disease in cardiac amyloidosis seems no more prevalent than in other people of similar age. Atrial infiltration definitely occurs, but CMR shows that much of the apparent atrial thickening in amyloidosis is interatrial fat. In later phases, atrial fibrillation, particularly coarse or flutter-like fibrillation, may be observed and thrombi may be seen in the left atrial appendage. The severe reduction in the atrial contraction characteristic of later stages is often associated with signs of very slow flow (‘‘smoke’’) in the left atrium and also occurs in patients in sinus rhythm. Serial imaging studies provide additional insight into the time course of amyloidosis. Swiftly changing cardiac hypertrophy is not common in cardiomyopathy in adult life (although late onset HCM is well known), but rapid changes over months in wall thickness and function should place AL amyloidosis high on the differential list. Although CMR-based morphological and functional assessment is probably more accurate than with echocardiography alone (with the important exception of diastolic dysfunction and strain measurement) [8], these features are non-specific and vary in prevalence until late phases of disease. Thus, in high pre-test probability scenarios, the
absence of these morphological and functional markers does not fully exclude cardiac amyloidosis [6].
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Tissue characterisation A key advantage of CMR is its unique ability to give information about the tissue composition by ‘‘myocardial tissue characterisation’’. The intrinsic signal (measured as the magnetic resonance parameters T1, T2 and T2*) from the myocardium without contrast agent can be used to distinguish normal from abnormal myocardium. Alternatively, the addition of an extrinsic gadolinium-based contrast agent Gd-DTPA (gadolinium diethylenetriamine penta-acetic acid) may reveal ‘‘extrinsic contrast’’ properties as in the late gadolinium enhancement technique (LGE). The gadolinium component alters the CMR signal, and the chelator makes it inert and determines the in vivo properties of the whole, determining the tracer behaviour [9]. These purely extracellular agents are small enough to pass across the vascular wall into the extracellular space, yet are large enough to not penetrate myocardial cells with intact membranes. The gadolinium accumulates passively in the gaps between cells through post-bolus tracer kinetics with an increased volume of distribution in the ‘‘scar’’
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tissue or in areas of amyloid deposition (areas of interstitial expansion) [10]. After gadolinium administration in normal tissue, the whole myocardium will have a diffuse lowering of T1. In scar/focal amyloid, there will be areas where the T1 is regionally detectably lower, which forms the basis of the LGE technique for qualitative detection of focal fibrosis (e.g. myocardial infarction). In diffuse infiltration, the whole myocardium will have substantially lower T1— which was difficult to assess until the development of the extracellular volume (ECV) technique. The typical ‘‘amyloid LGE pattern’’ is global subendocardial LGE in a non-coronary artery territory distribution with a dark blood pool, but this can vary [11]. Patterns vary in different series [10, 12–15] with some finding localised enhancement in a majority and diffuse transmural or patchy LGE in others [11, 16, 17] (Figs. 3, 4). Thus, although many authors refer to a ‘‘typical LGE pattern’’ in amyloid, current research suggests a more variable LGE pattern than previously reported, and more recent studies separating ATTR from AL are more informative. LGE (when classical) can be virtually pathognomonic and significantly more specific and sensitive than echo or CMR functional assessment. This can even be an apparently early finding— some patients are seen where the classical LGE appearance is present without hypertrophy (Fig. 3). However, traditional LGE imaging technique can be difficult to interpret in cardiac amyloid. It was designed for focal scar imaging—specifically myocardial infarction where there are large regional differences in gadolinium concentration between infarct and remote myocardium, which is normal. Infiltrative diseases, especially amyloid, that affect the entire myocardium may have no normal myocardium. This exposes a pitfall of the traditional approach in that the operator determining the optimal null point for the myocardium may erroneously choose to null the abnormal and not the normal myocardium. This can result in a serious risk of false-negative examinations (when the entire myocardium is involved but could appear as normal) or ‘‘wrong’’ LGE patterns (i.e. mirror image of the true pattern, with mid-myocardial patterns becoming subendocardial and vice versa), potentially contributing to the variable LGE patterns described (Fig. 4). The relatively new approach of phase-sensitive inversion recovery (PSIR) sequence [18], now available from almost all the CMR manufacturers, will reduce the need for an optimal null point setting, making LGE in cardiac amyloidosis far easier and operator-independent (Fig. 4). This approach is likely to improve the diagnostic and prognostic performance on ‘‘true’’ LGE patterns of cardiac amyloidosis, with the potential to reduce heterogeneity in the patterns reported. In our centre, PSIR is transforming the reliability of the LGE technique in amyloidosis and no patient with possible amyloidosis is scanned without using PSIR by default (Fig. 4).
However, the use of gadolinium is relatively contraindicated in patients with severe renal failure (estimated glomerular filtration rate, eGFR, \30 ml/min—a relatively common finding in patients with systemic AL amyloidosis). LGE in non-ischaemic cardiomyopathy, especially amyloid, is not easy to quantify, so it is not reliable for following up changes over time. Newer T1 mapping techniques may overcome these limitations. T1 mapping is a new technique where direct quantitative signal from the myocardium is measured, either pre-contrast (native T1) or post-contrast. Each pixel in the image is coded in colour, reflecting the absolute value of T1 (Fig. 5). Native myocardial T1 mapping therefore measures myocardial intrinsic signal, and T1 ‘‘maps’’ in a single breath-hold are now routine [19, 20]. Pathology changes native T1. Reduced T1 is uncommon, occurring only in iron overload [21] and fat infiltration such as Fabry disease (FD) [22, 23]. Increases in native T1 occur modestly in diffuse fibrosis, more in scar and substantially in amyloid and oedema—with good signal-to-noise ratio (Fig. 5). Native myocardial T1 mapping is associated in single centre studies with a high diagnostic accuracy for cardiac amyloidosis for both AL and ATTR when compared against patients with LVH from different causes such as aortic stenosis and HCM [22, 24, 25] (Fig. 5). This may find clinical utility particularly when gadolinium contrast is contraindicated. In both amyloid types, T1 tracks markers of systolic and diastolic function, mass and prognostic markers [25, 26]. T1 is an early disease marker, being elevated before the onset of LVH, presence of LGE or elevation in blood biomarkers. Finally, native T1 is able to track cardiac amyloid burden with the potential to become a useful tool to quantify cardiac amyloid and track changes over time [25]. There are three problems with native T1 mapping: firstly conceptually, it measures a composite myocardial signal from both interstitium and myocytes. Secondly, it does not differentiate fully the underlying processes—particularly oedema and amyloid (though it is not impossible that oedema may form part of the spectrum of myocardial amyloid infiltration), and thirdly, different CMR systems and sequences have different normal ranges. Standardisation is only now starting, but consensus guidelines [27] are now available. Normal T1s are higher when measured at 3T [28], with different sequences (‘‘SASHA’’ compared to other techniques), and typically with newer variants of mapping compared to older ones [29]. Current recommendations are for normal reference ranges to be defined locally, but this may change over time. The use of gadolinium-chelated contrast agents adds another dimension to CMR tissue characterisation with T1 mapping. Post-contrast T1 may be lower in cardiac disease, suggesting increased myocardial interstitial space. However,
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Heart Fail Rev Fig. 4 Late gadolinium enhancement (LGE) with magnitude (MAG) reconstruction (left panels) and LGE with phase-sensitive inversion recovery reconstruction (PSIR) (right panels). There is discordance between magnitude and PSIR reconstruction in the three examples. ECV mapping (not shown) can arbitrate—the areas of the highest ECV are the ones that should show LGE and PSIR are correct in all cases. Upper panels the MAG looks normal; the PSIR shows transmural LGE, concordant with an ECV here of [0.5, not shown. Middle panels the MAG (patchy more apical LGE) is a mirror of the PSIR (more apical). Lower panels: the MAG (subepicardial LGE, circle) is a mirror image of the true PSIR pattern
care is needed as the disease may have altered body composition (a higher percentage of body fat and, thus, a greater contrast dose per unit of total body extracellular water), reduced renal function or altered haematocrit. The fraction of tissue that is interstitial space is referred to as the extracellular volume (ECV). It can be calculated from the ratio of signal change in blood and myocardium after contrast administration and the blood contrast volume of distribution (equal to one minus haematocrit) (Fig. 6). Amyloidosis is the exemplar of interstitial disease, and this is reflected by massive ECV elevation in the patients with definite AL and ATTR cardiac amyloidosis [24, 30,
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31]. ECV is elevated also in patients where conventional clinical testing and LGE suggested no cardiac involvement, highlighting a potential role as early disease marker [24, 30]. Both T1 and ECV track a wide variety of markers of disease activity, such as cardiac function, blood biomarkers and patient functional performance. The greater elevation of ECV in ATTR (ECV being a more pure measure of amyloid burden) associated with an opposite trend in the native T1 signal (higher in AL, lower in ATTR) points to an additional pathological process that could contribute in AL amyloid to T1 elevation, the most likely explanation being myocardial oedema [30]. With the measurement of
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Fig. 5 CMR end-diastolic cine still (upper panel); ShMOLLI native T1 map (middle) and late gadolinium enhancement (LGE) images (lower). Left to right: healthy volunteer, hypertrophic cardiomyopathy (HCM), definite AL and definite ATTR patients. The native T1 maps
show significant elevation of native T1 (the myocardium is more red) in patients with ATTR and AL cardiac amyloidosis compared with normal subjects and patients with HCM. Adapted from Fontana et al. [25]
Fig. 6 A patient with left ventricular hypertrophy from aortic stenosis (upper panels) and cardiac amyloidosis (lower panels). From left to right: T1 maps pre-contrast (left), post-contrast centre left, LGE
centre right and extracellular volume (ECV) maps right. In the patient with cardiac amyloidosis on the ECV maps, there is evidence of massive interstitial volume expansion with ECV elevation
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the ECV, the total intracellular volume (representing the myocyte volume) can be derived, adding a third dimension to the tissue characterisation of patients with cardiac amyloidosis. ECV appears to be more robust, especially across different centres as it is a ratio of change of T1. Furthermore, high global ECVs can become very specific for amyloid: fibrosis cannot achieve remote (non-infarct) ECVs of above *0.4, implying that an ECV value greater than *0.4 in remote myocardium becomes highly specific, with the only other differential being global oedema—a newly reported but not well-understood phenomenon. Combined, native T1 mapping and ECV measurement may therefore over time add insight into cardiac amyloidosis at three different levels, i.e. infiltration (amyloid burden, ECV), oedema (native T1) and myocyte response (intracellular volume), providing a richer understanding of the pathophysiological mechanism.
Practical clinical use of CMR Diagnostic utility CMR adds value to the certainty of probable amyloidosis patients (Tables 1, 2). In the UK, where CMR is a welldeveloped national service, it has impacted referral patterns with a large national increase in the identification of patients with ATTR cardiac amyloidosis, particularly wild type, constraining resources in existing amyloid centres. Prospective studies with the aim of comparing the diagnostic accuracy of CMR against other approaches have not been done yet, but emerging experience suggests the following. The constellation of findings that lead one to suspect cardiac amyloidosis—e.g. an older adult patient (a bias in that AL amyloid affects individuals of any age) with echocardiographic findings of unexplained LVH, interatrial septal thickening, valvular fibrosis, pericardial effusion along with low voltage—is neither sufficiently sensitivity nor specific [32]. CMR, given its test characteristics, is
valuable in these clinical contexts where pre-test probability is intermediate. In patients with a high pre-test probability, early disease can be detected with more confidence. CMR adds value to the Mayo classification (or its equivalent in ATTR), and LGE can be pathognomonic of amyloidosis (but less so of specific subtype). CMR findings have increased accuracy compared with conventional echocardiographic imaging both in terms of specificity and sensitivity: for example, HCM may share features such as concentric hypertrophy, bi-atrial dilatation, reduced longitudinal function [33, 34] and decompensated biventricular restrictive disease [35], but both HCM and amyloid may have unique tissue characterisation findings [12, 16, 25, 36]. However, difficulties persist because of the variable pattern of LGE, and when pre-test probability is high, the presence of a normal standard LGE should not be used to exclude cardiac amyloid. Native myocardial T1 can be used to support the diagnosis or exclusion of cardiac amyloidosis. This can be done choosing different cut-offs, based on the clinical scenario, with specificity and sensitivity to diagnose or exclude cardiac amyloidosis, respectively. Ideally, the native T1 on subjects with end stage renal failure should be known as the comparator (rather than just healthy subjects), but this is not well studied at this time. CMR methods to distinguish types of cardiac amyloidosis Structural findings related to hypertrophy and functional characteristics differ according to amyloid subtype. Transthyretin amyloid usually manifests as disproportionately increased LV mass and interventricular septal thickness, larger atrial area, smaller cavity volumes and lower ejection fraction (within the normal range) than AL amyloid [16, 25], despite similar NYHA class and NT-proBNP levels. Tissue characteristics can be different in the different amyloid subtypes. The pattern and extent of LGE differ in ATTR and AL amyloidosis, with LGE typically more extensive in ATTR than in AL patients. RV LGE appears to be present in most ATTR amyloid cases, but in only a
Table 1 Benefits of CMR for cardiac amyloidosis Extracardiac anatomy: presence of pleural, pericardial effusions, ascites Quantification of volumes and mass (atrial volumes, end systolic and end-diastolic biventricular volumes, mass of both ventricles) Characterisation of the type of hypertrophy (concentric/eccentric, asymmetric/symmetric hypertrophy) Biventricular assessment of systolic function (ejection fraction, stroke volume and cardiac output) Tissue characterisation: 1. Native myocardial T1: elevated in both AL and ATTR cardiac amyloidosis. Diagnostic and prognostic utility 2. Late gadolinium enhancement: characteristic patterns are associated with high diagnostic accuracy 3. Extracellular volume: elevated in both AL and ATTR, indirect measure of amyloid burden. Diagnostic and prognostic utility
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Heart Fail Rev Table 2 Characteristics and clinical applications of CMR methods in cardiac amyloidosis CMR method
Description
Scanning time (min)
Need for contrast
Availability
Contraindication
Emerging applications in cardiac amyloid
Cines
Structural and functional assessment
*10
No
Widespread
General contraindication for CMR
Quantification of volumes, mass and systolic function
MAGLGE
Assessment of areas of interstitial expansion
*15
Yes
Widespread
General contraindication for CMR and low eGFR
Detection of scar/amyloid infiltration
PSIRLGE
Assessment of areas of interstitial expansion
*15
Yes
Widespread
General contraindication for CMR and low eGFR
Detection of scar/more robust for amyloid infiltration
Native T1
Measures native myocardial T1
*2
No
Limited
General contraindication for CMR
Diagnosis, prognosis and surrogate endpoint
ECV
Measures extracellular volume
*4
Yes
Limited
General contraindication for CMR and low eGFR. Needs haematocrit measurement
Diagnosis, prognosis and surrogate endpoint. More interscanner reproducible than native T1
majority with AL amyloid. A semi-quantitative LGE score combined with age and myocardial wall thickness had a reported sensitivity of 87 % and specificity of 96 % for distinguishing ATTR from AL amyloid [16]. Caveats to this score were the non-standardised approach used in the validation cohort of a retrospective study, use of different contrast agents, doses, acquisition times and LGE sequences which are all factors that have the potential to affect LGE patterns. T1 values are higher in AL amyloid compared with ATTR, whilst ECV is higher in ATTR than in AL [30]. This has the potential to be useful in the differentiation between the two types, especially if combined with a morphological and PSIR-LGE approach, but data are not yet available in this respect.
Prognostic ability Presence of LGE is predictive of prognosis in virtually all the cardiac pathologies, except for amyloidosis where studies have conflicting results and have been small and in AL only with non-standardised LGE approaches [10, 12, 13, 37]. As discussed above, the LGE can be problematic in amyloid with global infiltration and altered wash-in and wash-out kinetics. Specifically, patients exhibiting the most advanced interstitial infiltration can occasionally be portrayed as having no LGE (Fig. 4)—a misclassification that profoundly confounds prognostic studies. PSIR-LGE approach has the potential to shed light on this, clarifying the role of LGE in the stratification of patients with AL and ATTR cardiac amyloidosis [38].
Measurement of native myocardial T1 and ECV aids risk-stratifying patients with AL cardiac amyloidosis [39] (Fig. 7; Table 2). This probably adds incremental value over and above existing clinical markers. T1 and ECV measures by CMR may add clinical value when more traditional measures are confounded such as biomarkers in the setting of renal failure and LVH in the setting of concomitant hypertension. Incremental value appears present in cardiac AL amyloidosis regardless of treatment status and whether newly presenting or under established followup [39]; ATTR amyloidosis data are awaited. The use of these biomarkers to guide or tailor therapy and monitor response has not been explored yet. Surrogate endpoints in drug development Disease tracking is a fundamental step for drug development—the detection of biological effect (beneficial and off target) and dose ranging. No imaging modality has been shown to track changes over time in patients with cardiac amyloidosis, but T1 mapping has high potential. LV mass changes are a poor target endpoint as mass consists of myocyte volume (beneficial) and infiltration volume (adverse), and changes over time are not large compared with measurement error. Changes in function (stroke volume index rather than EF) have similar problems, with the additional confounder of deterioration in function associated with occurrence of atrial fibrillation rather than disease progression. T1 mapping has the potential to track structural changes over time at three different levels, i.e. infiltration (amyloid burden, ECV), possibly oedema (native T1) and myocyte response (intracellular volume),
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Fig. 7 Kaplan–Meier survival curves for a native myocardial T1 and b extracellular volume (ECVb). Adapted from Banypersad SM et al. [39]
providing a richer understanding of the pathophysiology of the response to treatment, but new data are awaited [40, 41]. ECV quantification has, however, been considered sufficiently robust to be used in several early-phase drug development studies.
CMR service delivery There are service delivery issues for cardiovascular magnetic resonance; CMR availability is not geographically evenly distributed, and there are some infrastructure issues within health care about service delivery across cardiology and radiology services. Furthermore, the typical peripheral involvement of cardiologists within the teams managing systemic amyloidosis, which are more traditionally renal, neural and haematology-based, interposes logistical challenges. Contrast should be used with caution when the eGFR is below 30 ml/min. The risks and benefits of this should be weighed against the alternatives particularly of doing nothing or of biopsy; bone tracer scans are also excellent for ATTR cardiac amyloidosis. The specific service delivery issues of CMR are unique to it, but other modalities too have their challenges. For example, the nonstandardisation and sophisticated echo stress and strain measurements limit their widespread adoption. Bone tracer scans are also excellent for ATTR cardiac amyloidosis, but the lack of availability of DPD within certain jurisdictions (e.g. USA), as well as limited head to head studies, constrains the evidence base.
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Conclusions Cardiovascular magnetic resonance is an excellent test to assess the structure and function of the heart, complementing echocardiography. Its tissue characterisation capabilities, however, are unique and may frequently provide a definitive and pathognomonic appearance of cardiac amyloidosis. CMR may provide strong indications of the fibril involved, ATTR or AL light chains, but rarely gives sufficient confidence to exclude AL definitively. The requirement for pursuing confirmation of AL amyloidosis is not diminished as a method of tracking cardiac involvement and of monitoring therapy. Over time, CMR is likely to become an established part of the routine care of amyloid patients, providing new insights into myocardial processes, introducing new appreciation of the myocyte response, broadening the concept of amyloidosis from solely infiltration and advancing drug development by detecting early therapeutic effect. It is likely to become an essential component within the standard diagnostic pathway for establishing the presence of cardiac infiltration without resorting to invasive cardiac biopsy. Conflict of interest
None.
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16. Dungu JN, Valencia O, Pinney JH, Gibbs SD, Rowczenio D, Gilbertson JA, Lachmann HJ, Wechalekar A, Gillmore JD, Whelan CJ, Hawkins PN, Anderson LJ (2014) CMR-based differentiation of AL and ATTR cardiac amyloidosis. JACC Cardiovasc Imaging 7:133–142 17. Perugini E, Guidalotti PL, Salvi F, Cooke RMT, Pettinato C, Riva L, Leone O, Farsad M, Ciliberti P, Bacchi-Reggiani L, Fallani F, Branzi A, Rapezzi C (2005) Non-invasive Etiologic diagnosis of cardiac amyloidosis using 99mTC-3,3-Diphophono-1,2-Propanodicarboxylic acid scintography. J Am Coll Cardiol 46:1076–1084 18. Kellman P, Arai AE, McVeigh ER, Aletras AH (2002) Phasesensitive inversion recovery for detecting myocardial infarction using gadolinium-delayed hyperenhancement. Magn Reson Med 47:372–383 19. Fontana M, White SK, Banypersad SM, Sado DM, Maestrini V, Flett AS, Piechnik SK, Neubauer S, Roberts N, Moon J (2012) 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 14:88 20. Kellman P, Hansen M (2014) T1-mapping in the heart: accuracy and precision. J Cardiovasc Magn Reson 16(1):2–20 21. Sado DM, Maestrini V, Piechnik SK, Banypersad SM, White SK, Flett AS, Robson MD, Neubauer S, Ariti C, Arai AE, Kellman P, Yamamura J, Schoennagel BP, Shah F, Davis B, Trompeter S, Walker M, Porter J, Moon JC (2014) Noncontrast myocardial T(1) mapping using cardiovascular magnetic resonance for iron overload. J Magn Reson Imaging epub 2014 Aug 8 22. Sado DM, White SK, Piechnik SK, Banypersad SM, Treibel TA, Captur G, Fontana M, Maestrini V, Flett AS, Robson MD, Lachmann RH, Murphy E, Mehta A, Hughes DA, Neubauer S, Elliott PM, Moon JC (2013) Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging 6:392–398 23. Thompson RB, Chow K, Khan A, Chan A, Shanks M, Paterson I, Oudit GY (2013) T1 mapping with cardiovascular MRI is highly sensitive for fabry disease independent of hypertrophy and sex. Circ Cardiovasc Imaging 6:637–645 24. Banypersad SM, Sado DN, Flett AS, Gibbs SD, Pinney JH, Maestrini V, Cox AT, Fontana M, Whelan CJ, Wechalekar AD, Hawkins PN, Moon JC (2013) Quantification of myocardial extracellular volume fraction in systemic AL amyloidosis: an equilibrium contrast cardiovascular magnetic resonance study. Circ Cardiovasc Imaging 6:34–39 25. Fontana M, Banypersad SM, Treibel TA, Maestrini V, Sado DM, White SK, Pica S, Castelletti S, Piechnik SK, Robson MD, Gilbertson JA, Rowczenio D, Hutt DF, Lachmann HJ, Wechalekar AD, Whelan CJ, Gillmore JD, Hawkins PN, Moon JC (2014) Native T1 mapping in transthyretin amyloidosis. JACC Cardiovasc Imaging 7:157–165 26. Karamitsos TD, Piechnik SK, Banypersad SM, Fontana M, Ntusi NB, Ferreira VM, Whelan CJ, Myerson SG, Robson MD, Hawkins PN, Neubauer S, Moon JC (2013) Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis. JACC Cardiovasc Imaging 6:488–497 27. Moon JC, Messroghli DR, Kellman P, Piechnik SK, Robson MD, Ugander M, Gatehouse PD, Arai AE, Friedrich MG, Neubauer S, Schulz-Menger J, Schelbert EB (2013) Society for cardiovascular Magnetic Resonance Imaging; Cardiovascular Magnetic Resonance Working Group of the European Society of Cardiology. Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement. J Cardiovasc Magn Reson 15(1):92
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Boni L, Rapezzi C (2009) Prognostic implications of the Doppler restrictive filling pattern in hypertrophic cardiomyopathy. Am J Cardiol 104:1727–1731 Kwong RY, Falk RH (2005) Cardioavascular magnetic resonance in cardiac amyloidosis. Circulation 111:122–124 White JA, Kim HW, Shah D, Fine N, Kim KY, Wendell DC, AlJaroudi W, Parker M, Patel M, Gwadry-Sridhar F, Judd RM, Kim RJ (2014) CMR imaging with rapid visual T1 assessment predicts mortality in patients suspected of cardiac amyloidosis. JACC Cardiovasc Imaging 7:143–156 Fontana M, Pica S, Reant P, Abdel-Gadir A, Treibel TA, Banypersad S, Maestrini V, Lane T, Lachmann HJ, Whelan CJ, Wechalekar AD, Manisty C, Herrey AS, Gillmore JD, Hawkins PN, Moon JC (2014) Cardiovascular magnetic resonance in cardiac amyloidosis: a 242 patient prospective study. Am Heart Assoc Sci Sess Abstract accepted Banypersad SM, Fontana M, Maestrini V, Sado DM, Captur G, Petrie A, Piechnik SK, Whelan CJ, Herrey AS, Gillmore JD, Lachmann HJ, Wechalekar AD, Hawkins PN, Moon JC (2014) T1 mapping and survival in systemic light-chain amyloidosis. Eur Heart J. doi:10.1093/eurheartj/ehu444 Alnylam (2013) Phase 2 study to evaluate ALN-TTRSC in patients with transthyretin (TTR) cardiac amyloidosis. http:// www.clinicaltrials.gov/ct2/show/NCT01981837?term=alnylam& rank=2 GlaxoSmithKline (2013) A study to evaluate the safety of GSK2398852 when co-administered with GSK2315698 in patients with systemic amyloidosis. http://clinicaltrials.gov/show/ NCT01777243 Leone O, Longhi S, Quarta C, Ragazzini T, De Giorgi L, Pasquale F, Potena L, Lovato L, Milandri A, Arpesella G, Rapezzi C (2012) New pathological insights into cardiac amyloidosis: implications for non-invasive diagnosis. Amyloid 19:99–105
Cardiovascular magnetic resonance for amyloidosis Marianna Fontana • Robin Chung • Philip N. Hawkins • James C. Moon
Ó Springer Science+Business Media New York 2014
Abstract Cardiac involvement drives the prognosis and treatment in systemic amyloid. Echocardiography, the mainstay of current cardiac imaging, defines cardiac structure and function. Echocardiography, in conjunction with clinical phenotype, electrocardiogram and biomarkers (brain natriuretic peptide and troponin), provides an assessment of the likelihood and extent of cardiac involvement. Two tests are transforming our understanding of cardiac amyloidosis, bone tracer scanning and cardiovascular magnetic resonance (CMR). CMR provides a ‘‘second opinion’’ on the heart’s structure and systolic function with better accuracy and more precision than echocardiography but is unable to assess diastolic function and is not as widely available. Where CMR adds unique advantages is in evaluating myocardial tissue characterisation. With administration of contrast, the latest type of late gadolinium enhancement imaging (phase-sensitive inversion recovery sequence) is highly sensitive and specific with images virtually pathognomonic for amyloidosis. CMR is also demonstrating that the range of structural and functional changes in cardiac amyloid is broader than
M. Fontana R. Chung J. C. Moon (&) The Heart Hospital Imaging Centre, 16–18 Westmoreland Street, London W1G 8PH, UK e-mail: [email protected] M. Fontana J. C. Moon Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK M. Fontana P. N. Hawkins National Amyloidosis Centre, Royal Free Hospital, University College London, London, UK
traditionally thought. CMR with T1 mapping, a relatively new CMR technique, can measure the amyloid burden and the myocyte response to infiltration (hypertrophy/cell loss) with advantages for tracking change (e.g. the wall thickness can stay the same but the composition can change) over time or during therapy. Such techniques hold great promise for advancing drug development in this arena and providing new prognostic insights. CMR with tissue characterisation is rewriting our understanding of cardiac amyloidosis and may lead to the development of new classification, therapies and prognostic systems. Keywords
Amyloidosis CMR T1 mapping
Introduction Systemic amyloidosis frequently involves the heart. Cardiac involvement drives prognosis and determines choice and effectiveness of therapy [1]. New treatments are pending that may specifically target cardiac involvement [2]. Whilst there may be amyloid in the degenerating aortic valve (origin: probably Apolipoprotein A1) [3] and in the atria (origin: atrial natriuretic peptide, ANP) [4], ventricular myocardium is primarily affected by immunoglobulin light chain (AL or primary systemic) type and transthyretin (ATTR) type amyloidosis—both wild type and mutant [5]. The traditional view is that cardiac amyloidosis (cardiac amyloid where the amyloid burden is sufficient to cause disease) is a disease of infiltration leading to adverse outcomes. The reality from experimental studies, biomarker analysis and imaging research is that the infiltration may trigger changes in interstitium and myocytes with resulting hypertrophy, myocyte loss and collagen deposition. Given that over half perhaps two-thirds of the heart can be
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amyloid in a living person, amyloid must be either remarkably benign, the myocardium remarkably adaptable or the heart has huge functional reserves. Nevertheless, it is the relentless and possible runaway nature of deposition that is the major problem.
history), clinical examination, ECG, 24-h Holter monitoring, other imaging investigations (echocardiography, bone tracer scanning), blood biomarkers (troponin, brain natriuretic peptides), myocardial biopsy and, importantly, other essential tests (such as free light chains and other organ biopsies including bone marrow) and genotyping.
Cardiac investigations (cardiovascular magnetic resonance in context)
CMR
Detecting and quantifying cardiac amyloid infiltration and the myocardial response are a crucial step in understanding the disease. The gold standard for the diagnosis and subtyping of cardiac amyloidosis is histology (Fig. 1), ideally with specialist analysis (immunofixation/microdissection for proteomics), but cardiac biopsy carries a risk of morbidity and mortality. Furthermore, the patchiness of the cardiac amyloid deposition makes this approach an unreliable method to track serial change over time (Fig. 1). Cardiovascular magnetic resonance (CMR) can measure the structure and function of the heart and uniquely enables whole heart myocardial tissue characterisation. For many important parameters, it is a more reproducible modality, meaning that change (with therapy, with progression or occasionally with regression) is more easily detected. However, CMR, like all other tests, is just one test within the portfolio of history taking (cardiac, multisystem, family
CMR uses a superconducting magnet with ECG gating to investigate the heart, gaining insight into the extracardiac anatomy, cardiac structure, function and specific characterisations of myocardial tissue. CMR may have high sensitivity and specificity, but the diagnostic yield and importance of findings depend on the pre-test probability. Advanced cardiac amyloidosis is easy to detect by any technique: the detection of early cardiac involvement and the distinction from other phenocopies is more difficult. CMR, like other tests, should therefore be interpreted in the clinical context. Specific differentials or disease processes that may raise diagnostic problems and confounders are comorbidities such as age, renal failure, diabetes, hypertension and another cardiomyopathy such as hypertrophic cardiomyopathy (HCM) and the presence of dual pathology—for example aortic stenosis and wild-type ATTR amyloidosis.
Fig. 1 Left panes: examples of the different degrees of amyloid infiltration (in black) with comparable left ventricular wall thickness: a extensive and diffuse infiltration; b subendocardial infiltration
(Adapted from Leone et al. [42]). Right panels: endomyocardial biopsy with immunochemistry of a patient with AL amyloidosis c and a patient with ATTR amyloidosis d
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Traditionally, cardiac amyloidosis has been thought to be characterised by concentric and symmetric hypertrophy of the left ventricle as opposed to apical or asymmetric wall thickening in HCM (Fig. 3). However, recent work
documents concentric left ventricular hypertrophy (LVH) in 59 % of patients with cardiac amyloidosis, eccentric LVH or concentric remodelling in 33 % and normal geometry in the remaining 8 % [6]. Cardiac amyloidosis may present with symmetric or asymmetric, concentric or eccentric hypertrophy (Fig. 3). Hypertrophy may be disproportionately greater than in hypertension (e.g. greater than *17 mm) and is more prominent in ATTR than in AL amyloid. Right ventricular (RV) involvement with hypertrophy is frequent—the RV end systolic thickness may be up to 1 cm. A few cases have been observed with a dilated cardiomyopathy phenotype (again with classical tissue characterisation findings) (Fig. 3), and occasionally, patients have outflow tract obstruction. Thus, although many cases are characteristic, the full range of morphological findings in amyloid is broad. Traditional markers such as ejection fraction may be normal even into the late phase of disease because it is a poor measure of systolic function in patients with concentric remodelling. Long axis function (typically biventricular) declines early, mainly at the level of the basal segments. The reduction, in many cases to effectively zero longitudinal function, is associated with small cavity size, decreased stroke volume and reduced cardiac output [7]. The indexed stroke volume, usually severely reduced, is therefore a better measure of systolic function than the ejection fraction, and we would recommend scrutinising it in reports of possible cardiac amyloid.
Fig. 2 Examples of frequent extracardiac findings in patients with cardiac amyloidosis. a Pleural and pericardial effusions. b Ascites without pleural effusions. c Right pleural effusion. d Lardaceous fatty
liver with its featureless hypovascular appearance. e Tortuous and dilated thoracic aorta, frequently seen in hypertension, one of the main differentials. f Patchy lung changes (non-specific by CMR)
CMR findings in amyloidosis Extracardiac anatomy Cardiac amyloidosis is frequently associated with other abnormalities. Pleural effusions are common, as is ascites in advanced disease (Fig. 2). The presence of effusions and ascites when there is preserved systolic function (e.g. a normal ejection fraction) is one clue to the presence of cardiac amyloidosis. Additionally, the presence of ascites, indicative of right heart failure, is often observed in the later phases of cardiac amyloidosis (Fig. 2). Patchy lung changes are not infrequently seen, but many patients are elderly, and CMR is not adequate to diagnose lung infiltration (Fig. 2). Occasionally, the presence of increased gas in the bowel or dilated oesophagus from autonomic dysfunction can be seen. Similarly, liver changes are occasionally seen—fatty liver with its featureless hypovascular appearance is an occasional finding in patients with known AL amyloidosis (Fig. 2). Morphology, function and anatomy
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Fig. 3 Left ventricular remodelling phenotypes in cardiac amyloidosis. For each pattern, there is an example of a cine four chamber view and a short axis late gadolinium enhancement. Left upper panel: symmetric hypertrophy, traditionally considered the characteristic pattern. Right upper panel: asymmetric hypertrophy, recently proven
to be highly prevalent in cardiac amyloidosis. Left lower panel: dilated cardiomyopathy phenotype (rarely described in few cases). Right lower panel: no left ventricular hypertrophy with late gad features of amyloidosis, a less uncommon finding that is hard to detect without tissue characterisation
CMR is less adept than echocardiography for diastolic function assessment. Valvular disease in cardiac amyloidosis seems no more prevalent than in other people of similar age. Atrial infiltration definitely occurs, but CMR shows that much of the apparent atrial thickening in amyloidosis is interatrial fat. In later phases, atrial fibrillation, particularly coarse or flutter-like fibrillation, may be observed and thrombi may be seen in the left atrial appendage. The severe reduction in the atrial contraction characteristic of later stages is often associated with signs of very slow flow (‘‘smoke’’) in the left atrium and also occurs in patients in sinus rhythm. Serial imaging studies provide additional insight into the time course of amyloidosis. Swiftly changing cardiac hypertrophy is not common in cardiomyopathy in adult life (although late onset HCM is well known), but rapid changes over months in wall thickness and function should place AL amyloidosis high on the differential list. Although CMR-based morphological and functional assessment is probably more accurate than with echocardiography alone (with the important exception of diastolic dysfunction and strain measurement) [8], these features are non-specific and vary in prevalence until late phases of disease. Thus, in high pre-test probability scenarios, the
absence of these morphological and functional markers does not fully exclude cardiac amyloidosis [6].
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Tissue characterisation A key advantage of CMR is its unique ability to give information about the tissue composition by ‘‘myocardial tissue characterisation’’. The intrinsic signal (measured as the magnetic resonance parameters T1, T2 and T2*) from the myocardium without contrast agent can be used to distinguish normal from abnormal myocardium. Alternatively, the addition of an extrinsic gadolinium-based contrast agent Gd-DTPA (gadolinium diethylenetriamine penta-acetic acid) may reveal ‘‘extrinsic contrast’’ properties as in the late gadolinium enhancement technique (LGE). The gadolinium component alters the CMR signal, and the chelator makes it inert and determines the in vivo properties of the whole, determining the tracer behaviour [9]. These purely extracellular agents are small enough to pass across the vascular wall into the extracellular space, yet are large enough to not penetrate myocardial cells with intact membranes. The gadolinium accumulates passively in the gaps between cells through post-bolus tracer kinetics with an increased volume of distribution in the ‘‘scar’’
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tissue or in areas of amyloid deposition (areas of interstitial expansion) [10]. After gadolinium administration in normal tissue, the whole myocardium will have a diffuse lowering of T1. In scar/focal amyloid, there will be areas where the T1 is regionally detectably lower, which forms the basis of the LGE technique for qualitative detection of focal fibrosis (e.g. myocardial infarction). In diffuse infiltration, the whole myocardium will have substantially lower T1— which was difficult to assess until the development of the extracellular volume (ECV) technique. The typical ‘‘amyloid LGE pattern’’ is global subendocardial LGE in a non-coronary artery territory distribution with a dark blood pool, but this can vary [11]. Patterns vary in different series [10, 12–15] with some finding localised enhancement in a majority and diffuse transmural or patchy LGE in others [11, 16, 17] (Figs. 3, 4). Thus, although many authors refer to a ‘‘typical LGE pattern’’ in amyloid, current research suggests a more variable LGE pattern than previously reported, and more recent studies separating ATTR from AL are more informative. LGE (when classical) can be virtually pathognomonic and significantly more specific and sensitive than echo or CMR functional assessment. This can even be an apparently early finding— some patients are seen where the classical LGE appearance is present without hypertrophy (Fig. 3). However, traditional LGE imaging technique can be difficult to interpret in cardiac amyloid. It was designed for focal scar imaging—specifically myocardial infarction where there are large regional differences in gadolinium concentration between infarct and remote myocardium, which is normal. Infiltrative diseases, especially amyloid, that affect the entire myocardium may have no normal myocardium. This exposes a pitfall of the traditional approach in that the operator determining the optimal null point for the myocardium may erroneously choose to null the abnormal and not the normal myocardium. This can result in a serious risk of false-negative examinations (when the entire myocardium is involved but could appear as normal) or ‘‘wrong’’ LGE patterns (i.e. mirror image of the true pattern, with mid-myocardial patterns becoming subendocardial and vice versa), potentially contributing to the variable LGE patterns described (Fig. 4). The relatively new approach of phase-sensitive inversion recovery (PSIR) sequence [18], now available from almost all the CMR manufacturers, will reduce the need for an optimal null point setting, making LGE in cardiac amyloidosis far easier and operator-independent (Fig. 4). This approach is likely to improve the diagnostic and prognostic performance on ‘‘true’’ LGE patterns of cardiac amyloidosis, with the potential to reduce heterogeneity in the patterns reported. In our centre, PSIR is transforming the reliability of the LGE technique in amyloidosis and no patient with possible amyloidosis is scanned without using PSIR by default (Fig. 4).
However, the use of gadolinium is relatively contraindicated in patients with severe renal failure (estimated glomerular filtration rate, eGFR, \30 ml/min—a relatively common finding in patients with systemic AL amyloidosis). LGE in non-ischaemic cardiomyopathy, especially amyloid, is not easy to quantify, so it is not reliable for following up changes over time. Newer T1 mapping techniques may overcome these limitations. T1 mapping is a new technique where direct quantitative signal from the myocardium is measured, either pre-contrast (native T1) or post-contrast. Each pixel in the image is coded in colour, reflecting the absolute value of T1 (Fig. 5). Native myocardial T1 mapping therefore measures myocardial intrinsic signal, and T1 ‘‘maps’’ in a single breath-hold are now routine [19, 20]. Pathology changes native T1. Reduced T1 is uncommon, occurring only in iron overload [21] and fat infiltration such as Fabry disease (FD) [22, 23]. Increases in native T1 occur modestly in diffuse fibrosis, more in scar and substantially in amyloid and oedema—with good signal-to-noise ratio (Fig. 5). Native myocardial T1 mapping is associated in single centre studies with a high diagnostic accuracy for cardiac amyloidosis for both AL and ATTR when compared against patients with LVH from different causes such as aortic stenosis and HCM [22, 24, 25] (Fig. 5). This may find clinical utility particularly when gadolinium contrast is contraindicated. In both amyloid types, T1 tracks markers of systolic and diastolic function, mass and prognostic markers [25, 26]. T1 is an early disease marker, being elevated before the onset of LVH, presence of LGE or elevation in blood biomarkers. Finally, native T1 is able to track cardiac amyloid burden with the potential to become a useful tool to quantify cardiac amyloid and track changes over time [25]. There are three problems with native T1 mapping: firstly conceptually, it measures a composite myocardial signal from both interstitium and myocytes. Secondly, it does not differentiate fully the underlying processes—particularly oedema and amyloid (though it is not impossible that oedema may form part of the spectrum of myocardial amyloid infiltration), and thirdly, different CMR systems and sequences have different normal ranges. Standardisation is only now starting, but consensus guidelines [27] are now available. Normal T1s are higher when measured at 3T [28], with different sequences (‘‘SASHA’’ compared to other techniques), and typically with newer variants of mapping compared to older ones [29]. Current recommendations are for normal reference ranges to be defined locally, but this may change over time. The use of gadolinium-chelated contrast agents adds another dimension to CMR tissue characterisation with T1 mapping. Post-contrast T1 may be lower in cardiac disease, suggesting increased myocardial interstitial space. However,
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care is needed as the disease may have altered body composition (a higher percentage of body fat and, thus, a greater contrast dose per unit of total body extracellular water), reduced renal function or altered haematocrit. The fraction of tissue that is interstitial space is referred to as the extracellular volume (ECV). It can be calculated from the ratio of signal change in blood and myocardium after contrast administration and the blood contrast volume of distribution (equal to one minus haematocrit) (Fig. 6). Amyloidosis is the exemplar of interstitial disease, and this is reflected by massive ECV elevation in the patients with definite AL and ATTR cardiac amyloidosis [24, 30,
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31]. ECV is elevated also in patients where conventional clinical testing and LGE suggested no cardiac involvement, highlighting a potential role as early disease marker [24, 30]. Both T1 and ECV track a wide variety of markers of disease activity, such as cardiac function, blood biomarkers and patient functional performance. The greater elevation of ECV in ATTR (ECV being a more pure measure of amyloid burden) associated with an opposite trend in the native T1 signal (higher in AL, lower in ATTR) points to an additional pathological process that could contribute in AL amyloid to T1 elevation, the most likely explanation being myocardial oedema [30]. With the measurement of
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Fig. 5 CMR end-diastolic cine still (upper panel); ShMOLLI native T1 map (middle) and late gadolinium enhancement (LGE) images (lower). Left to right: healthy volunteer, hypertrophic cardiomyopathy (HCM), definite AL and definite ATTR patients. The native T1 maps
show significant elevation of native T1 (the myocardium is more red) in patients with ATTR and AL cardiac amyloidosis compared with normal subjects and patients with HCM. Adapted from Fontana et al. [25]
Fig. 6 A patient with left ventricular hypertrophy from aortic stenosis (upper panels) and cardiac amyloidosis (lower panels). From left to right: T1 maps pre-contrast (left), post-contrast centre left, LGE
centre right and extracellular volume (ECV) maps right. In the patient with cardiac amyloidosis on the ECV maps, there is evidence of massive interstitial volume expansion with ECV elevation
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the ECV, the total intracellular volume (representing the myocyte volume) can be derived, adding a third dimension to the tissue characterisation of patients with cardiac amyloidosis. ECV appears to be more robust, especially across different centres as it is a ratio of change of T1. Furthermore, high global ECVs can become very specific for amyloid: fibrosis cannot achieve remote (non-infarct) ECVs of above *0.4, implying that an ECV value greater than *0.4 in remote myocardium becomes highly specific, with the only other differential being global oedema—a newly reported but not well-understood phenomenon. Combined, native T1 mapping and ECV measurement may therefore over time add insight into cardiac amyloidosis at three different levels, i.e. infiltration (amyloid burden, ECV), oedema (native T1) and myocyte response (intracellular volume), providing a richer understanding of the pathophysiological mechanism.
Practical clinical use of CMR Diagnostic utility CMR adds value to the certainty of probable amyloidosis patients (Tables 1, 2). In the UK, where CMR is a welldeveloped national service, it has impacted referral patterns with a large national increase in the identification of patients with ATTR cardiac amyloidosis, particularly wild type, constraining resources in existing amyloid centres. Prospective studies with the aim of comparing the diagnostic accuracy of CMR against other approaches have not been done yet, but emerging experience suggests the following. The constellation of findings that lead one to suspect cardiac amyloidosis—e.g. an older adult patient (a bias in that AL amyloid affects individuals of any age) with echocardiographic findings of unexplained LVH, interatrial septal thickening, valvular fibrosis, pericardial effusion along with low voltage—is neither sufficiently sensitivity nor specific [32]. CMR, given its test characteristics, is
valuable in these clinical contexts where pre-test probability is intermediate. In patients with a high pre-test probability, early disease can be detected with more confidence. CMR adds value to the Mayo classification (or its equivalent in ATTR), and LGE can be pathognomonic of amyloidosis (but less so of specific subtype). CMR findings have increased accuracy compared with conventional echocardiographic imaging both in terms of specificity and sensitivity: for example, HCM may share features such as concentric hypertrophy, bi-atrial dilatation, reduced longitudinal function [33, 34] and decompensated biventricular restrictive disease [35], but both HCM and amyloid may have unique tissue characterisation findings [12, 16, 25, 36]. However, difficulties persist because of the variable pattern of LGE, and when pre-test probability is high, the presence of a normal standard LGE should not be used to exclude cardiac amyloid. Native myocardial T1 can be used to support the diagnosis or exclusion of cardiac amyloidosis. This can be done choosing different cut-offs, based on the clinical scenario, with specificity and sensitivity to diagnose or exclude cardiac amyloidosis, respectively. Ideally, the native T1 on subjects with end stage renal failure should be known as the comparator (rather than just healthy subjects), but this is not well studied at this time. CMR methods to distinguish types of cardiac amyloidosis Structural findings related to hypertrophy and functional characteristics differ according to amyloid subtype. Transthyretin amyloid usually manifests as disproportionately increased LV mass and interventricular septal thickness, larger atrial area, smaller cavity volumes and lower ejection fraction (within the normal range) than AL amyloid [16, 25], despite similar NYHA class and NT-proBNP levels. Tissue characteristics can be different in the different amyloid subtypes. The pattern and extent of LGE differ in ATTR and AL amyloidosis, with LGE typically more extensive in ATTR than in AL patients. RV LGE appears to be present in most ATTR amyloid cases, but in only a
Table 1 Benefits of CMR for cardiac amyloidosis Extracardiac anatomy: presence of pleural, pericardial effusions, ascites Quantification of volumes and mass (atrial volumes, end systolic and end-diastolic biventricular volumes, mass of both ventricles) Characterisation of the type of hypertrophy (concentric/eccentric, asymmetric/symmetric hypertrophy) Biventricular assessment of systolic function (ejection fraction, stroke volume and cardiac output) Tissue characterisation: 1. Native myocardial T1: elevated in both AL and ATTR cardiac amyloidosis. Diagnostic and prognostic utility 2. Late gadolinium enhancement: characteristic patterns are associated with high diagnostic accuracy 3. Extracellular volume: elevated in both AL and ATTR, indirect measure of amyloid burden. Diagnostic and prognostic utility
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Heart Fail Rev Table 2 Characteristics and clinical applications of CMR methods in cardiac amyloidosis CMR method
Description
Scanning time (min)
Need for contrast
Availability
Contraindication
Emerging applications in cardiac amyloid
Cines
Structural and functional assessment
*10
No
Widespread
General contraindication for CMR
Quantification of volumes, mass and systolic function
MAGLGE
Assessment of areas of interstitial expansion
*15
Yes
Widespread
General contraindication for CMR and low eGFR
Detection of scar/amyloid infiltration
PSIRLGE
Assessment of areas of interstitial expansion
*15
Yes
Widespread
General contraindication for CMR and low eGFR
Detection of scar/more robust for amyloid infiltration
Native T1
Measures native myocardial T1
*2
No
Limited
General contraindication for CMR
Diagnosis, prognosis and surrogate endpoint
ECV
Measures extracellular volume
*4
Yes
Limited
General contraindication for CMR and low eGFR. Needs haematocrit measurement
Diagnosis, prognosis and surrogate endpoint. More interscanner reproducible than native T1
majority with AL amyloid. A semi-quantitative LGE score combined with age and myocardial wall thickness had a reported sensitivity of 87 % and specificity of 96 % for distinguishing ATTR from AL amyloid [16]. Caveats to this score were the non-standardised approach used in the validation cohort of a retrospective study, use of different contrast agents, doses, acquisition times and LGE sequences which are all factors that have the potential to affect LGE patterns. T1 values are higher in AL amyloid compared with ATTR, whilst ECV is higher in ATTR than in AL [30]. This has the potential to be useful in the differentiation between the two types, especially if combined with a morphological and PSIR-LGE approach, but data are not yet available in this respect.
Prognostic ability Presence of LGE is predictive of prognosis in virtually all the cardiac pathologies, except for amyloidosis where studies have conflicting results and have been small and in AL only with non-standardised LGE approaches [10, 12, 13, 37]. As discussed above, the LGE can be problematic in amyloid with global infiltration and altered wash-in and wash-out kinetics. Specifically, patients exhibiting the most advanced interstitial infiltration can occasionally be portrayed as having no LGE (Fig. 4)—a misclassification that profoundly confounds prognostic studies. PSIR-LGE approach has the potential to shed light on this, clarifying the role of LGE in the stratification of patients with AL and ATTR cardiac amyloidosis [38].
Measurement of native myocardial T1 and ECV aids risk-stratifying patients with AL cardiac amyloidosis [39] (Fig. 7; Table 2). This probably adds incremental value over and above existing clinical markers. T1 and ECV measures by CMR may add clinical value when more traditional measures are confounded such as biomarkers in the setting of renal failure and LVH in the setting of concomitant hypertension. Incremental value appears present in cardiac AL amyloidosis regardless of treatment status and whether newly presenting or under established followup [39]; ATTR amyloidosis data are awaited. The use of these biomarkers to guide or tailor therapy and monitor response has not been explored yet. Surrogate endpoints in drug development Disease tracking is a fundamental step for drug development—the detection of biological effect (beneficial and off target) and dose ranging. No imaging modality has been shown to track changes over time in patients with cardiac amyloidosis, but T1 mapping has high potential. LV mass changes are a poor target endpoint as mass consists of myocyte volume (beneficial) and infiltration volume (adverse), and changes over time are not large compared with measurement error. Changes in function (stroke volume index rather than EF) have similar problems, with the additional confounder of deterioration in function associated with occurrence of atrial fibrillation rather than disease progression. T1 mapping has the potential to track structural changes over time at three different levels, i.e. infiltration (amyloid burden, ECV), possibly oedema (native T1) and myocyte response (intracellular volume),
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Fig. 7 Kaplan–Meier survival curves for a native myocardial T1 and b extracellular volume (ECVb). Adapted from Banypersad SM et al. [39]
providing a richer understanding of the pathophysiology of the response to treatment, but new data are awaited [40, 41]. ECV quantification has, however, been considered sufficiently robust to be used in several early-phase drug development studies.
CMR service delivery There are service delivery issues for cardiovascular magnetic resonance; CMR availability is not geographically evenly distributed, and there are some infrastructure issues within health care about service delivery across cardiology and radiology services. Furthermore, the typical peripheral involvement of cardiologists within the teams managing systemic amyloidosis, which are more traditionally renal, neural and haematology-based, interposes logistical challenges. Contrast should be used with caution when the eGFR is below 30 ml/min. The risks and benefits of this should be weighed against the alternatives particularly of doing nothing or of biopsy; bone tracer scans are also excellent for ATTR cardiac amyloidosis. The specific service delivery issues of CMR are unique to it, but other modalities too have their challenges. For example, the nonstandardisation and sophisticated echo stress and strain measurements limit their widespread adoption. Bone tracer scans are also excellent for ATTR cardiac amyloidosis, but the lack of availability of DPD within certain jurisdictions (e.g. USA), as well as limited head to head studies, constrains the evidence base.
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Conclusions Cardiovascular magnetic resonance is an excellent test to assess the structure and function of the heart, complementing echocardiography. Its tissue characterisation capabilities, however, are unique and may frequently provide a definitive and pathognomonic appearance of cardiac amyloidosis. CMR may provide strong indications of the fibril involved, ATTR or AL light chains, but rarely gives sufficient confidence to exclude AL definitively. The requirement for pursuing confirmation of AL amyloidosis is not diminished as a method of tracking cardiac involvement and of monitoring therapy. Over time, CMR is likely to become an established part of the routine care of amyloid patients, providing new insights into myocardial processes, introducing new appreciation of the myocyte response, broadening the concept of amyloidosis from solely infiltration and advancing drug development by detecting early therapeutic effect. It is likely to become an essential component within the standard diagnostic pathway for establishing the presence of cardiac infiltration without resorting to invasive cardiac biopsy. Conflict of interest
None.
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