Light chain amyloidosis, also known as primary systemic amyloidosis, is the most common type of amyloidosis. This is a plasma cell dyscrasia characterized by deposition of amyloidogenic chains in the extracellular space, causing a lesion in this tissue affected. Cardiac dysfunction is seen in up to 50% of patients with amyloidosis,9 and this type of amyloidosis can cause restrictive cardiomyopathy. Congestive heart failure is quite common, caused by thickening and lack of dilatation of the left ventricle, detected by echocardiography.10 Myocardial dysfunction caused by amyloidosis can be evaluated by measurement of brain natriuretic peptide (BNP) and troponin levels. Right heart failure is frequently aggravated by the concomitant presence of nephrotic syndrome, observed in 30-50% of the cases. Cardiomyopathy is the most aggressive manifestation of amyloidosis, and the main cause of poor prognosis and death. Cardiac amyloidosis has also been associated with multiple myeloma, which can also be evaluated.2^,9^,11^,12

Hereditary systemic amyloidosis is a dominant autosomal disease caused by deposition of amyloid fibrils resulting from mutations in genes that encode transthyretin and apolipoprotein A-I, A-II, fibrinogen, gelsolin, cystatin C and lysozyme. Transthyretin is mainly produced by the liver and participates in the transport of thyroxine and retinol. Hereditary systemic amyloidosis is caused by 100 different mutations in the DNA of transthyretin, generating a heterogeneity of penetrance. Clinical presentation of the disease includes cardiomyopathy, nephropathy and neuropathy. Although transthyretin-related cardiac amyloidosis is less aggressive than immunoglobulin light chain amyloidosis, hereditary systemic amyloidosis is also a cause of significant symptoms of heart failure.13^,14

Senile systemic amyloidosis, also related to transthyretin, is not hereditary and generally occurs after the seventh decade of life. This presentation of amyloidosis can be called as senile systemic or wild type amyloidosis. Similar to other types of the disease, in senile systemic amyloidosis, amyloid deposition can occur in several tissues such as cardiac, hepatic, and pancreatic tissues. Senile systemic amyloidosis is usually preceded by heart failure approximately 3-5 years before. Patients are mostly men, older than 70 years. The diagnosis of the disease had been probably underestimated; with advances in the diagnosis provided by CMR, from 2000 to 2009, the number of patients seen at amyloidosis centers in the United Kingdom increased by approximately 6.5%.5^-9^,15

Recent reports have described cases of senile amyloidosis in patients with heart failure with increased ejection fraction, highlighting the importance of clinical cardiologists considering the disease in suspected cases. Clinical suspicion is higher in cases of heart failure with increased ejection fraction associated with infiltrative cardiomyopathy revealed by cardiac imaging tests.16

In amyloidosis patients, particularly in those with light chain amyloidosis, electrocardiography usually reveals low voltage of the QRS complexes which, together with myocardial thickening increases the suspicion of cardiac amyloidosis. One hypothesis of voltage decrease is related with amyloid infiltration, which would cause a decrease in cardiac muscle cells. Atrioventricular block, atrial flutter and ventricular tachycardia have been also reported in these patients.9^,14^,17^,18

When cardiac amyloidosis is suspected, echocardiography is usually the first imaging test ordered by the physician. The use of two-dimensional speckle tracking technique has been used to detect subclinical or initial changes of the disease, which may help in the treatment of the patients.19 At initial stages, diagnosis of amyloidosis may be confounded with parietal hypertrophy, as in hypertrophic cardiomyopathy. However, characteristic findings are more frequently seen at more advanced stages of the disease and are observer-dependent. Common findings include increased ventricular parietal thickness, frequently involving the right ventricle, decreased ejection fraction20^,21 and thickening of valve and interatrial septum. Echocardiography may show wall thickening, especially basal, with high birefringence in the apical area (apical sparing) of the amyloid deposits, in addition to involvement of valves and papillary muscles.18

Immunoglobulin light chain amyloidosis is commonly associated with increased levels of troponin and BNP and N-terminal pro-B-type natriuretic peptide (NT-proBNP), which is not observed in transthyretin amyloidosis. This is important for patients with some renal dysfunction, since natriuretic peptides require renal excretion. Increased NT-proBNP in patients with systemic amyloidosis is predictive of cardiac disease.22 More recently, high-sensitivity troponin has been used as a marker of morbidity and mortality.23 At diagnosis, measurements of natriuretic peptide and troponin are used for risk stratification of patients.

Scintigraphy is performed with intravenous injection of iodine-123 (123I) for locating amyloid deposit in different organs, including liver, kidney, spleen, adrenal glands, and bones. Thus, this is not an adequate technique for cardiac evaluation in amyloidosis.24 On the other hand, the use of other markers - 99m Technetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) - has been suggested to specifically locate cardiac amyloid in transthyretin amyloidosis and considered the gold standard for the diagnosis of this condition.25^-28

In the analysis of ventricular, segmental and total activity, gradient-recalled echo (GRE) and balanced steady-state free precession (SSFP) imaging is the most used sequence. The sequence is added to the electrocardiographic tracings by segmented K-space technique, eliminating motion artifacts.30

Segmented K-space GRE sequences allow acquisition of many frames during the cardiac cycle in a dissection plane. Presentation of the frames in sequence allows dynamic, motion visualization of the heart during cardiac cycle, due to real-time interpolation of the R-R interval in the ECG. Strengths of the technique include optimal temporal resolution, the clear definition of endocardial and epicardial borders and acquisition of bright-blood cine images. Also, images can be obtained in any geometric plan.31

Similarly, fast-GRE images, previously used for functional evaluation, are more sensitive to turbulent flow, and are valuable for assessment of stenosis and valve insufficiency. Nevertheless, the method produces worse specification between the myocardium and blood in cardiac cavities when compared with SSFP.32^,33 A new sequencing technique, known as "real time" sequencing has high diagnostic quality and can be used for patients with arrhythmias and patients with inability to sustain apnea.4

In the assessment of cardiac amyloidosis, characterization of morphology and function of the disease by cine-MR (Figure 1) is crucial, especially in established disease. This is a widely used technique and is used in all protocols of cardiac study by MR.

Figure 1

Myocardial tagging by CMR provides a noninvasive, powerful method to quantify segmental and diastolic functions. The development of the technology, particularly of the sequences, type of devices and analysis software have facilitated the use of this technique. This will be very useful to assess patients' conditions and course of the disease.

Myocardial tagging uses a fast gradient echo sequence with saturation lines, creating a grid on the images that moves with cardiac motion, allowing an objective quantification of myocardial contraction during cardiac cycle (myocardial strain).34^-36

Myocardial tagging (Figure 2) should be used for the diagnosis of initial or subclinical amyloidosis. In addition, the technique may detect longitudinal or circumferential functional changes in individuals with mutations but without a clear phenotype determined by other techniques.37^,38 We understand that one limitation for the use of myocardial tagging in many centers is the lack of specific softwares for analysis, but we believe in the benefits of the implementation of the technology.

Figure 2

In the analysis of the anatomy the heart and large vessels, double-inversion fast spin-echo is the most used sequence. It is based on the acquisition of fast spin-echo combined with double inversion preparation pulse - the first applied to the whole tissue (nonselective) and the second, slice-selective. This technique has high spatial resolution (selective); blood is dark in the images (null signal) and, because of that, the technique is known as "black-blood" imaging. This occurs because fast moving tissues, similarly to blood, when moving outside the slice of interest, do not produce any signal, while stable tissues or slow-moving tissues, like the myocardium, produce a high signal. However, endocardial borders (between the blood and the myocardium) are well defined. This sequence has a segmented acquisition, obtained from final expiratory apnea, synchronized with the electrocardiogram (ECG). An acceptable change, known as triple inversion recovery, is the addition of a third saturation pulse, to suppress the signal from the adipose tissue (fat saturation), which may help in the diagnosis in certain situations, such as characterization of cardiac tumors.30^,31^,34

These techniques add little to the assessment of amyloidosis, and often are not included in the protocols to optimize the time of test execution. Nevertheless, in some situations, differential diagnosis is important, and situations that require evaluation of the pericardium, better tissue or even morphological characterization can be added to the basic protocol.

Myocardial perfusion imaging using CMR is obtained by the first pass of contrast (gadolinium) into ventricular cavities and then into the myocardium. One of the most frequently used methods constitutes a hybrid of fast gradient-echo and ultra-fast echo- planar imaging preceded by a saturation pulse from the tissue signal. This allows the acquisition of images in several planes every one-two heartbeats, repeatedly over a 60-second time period, along with the contrast passage. Myocardial perfusion can be used at rest or with pharmacological stress using adenosine, dipyridamole or regadenoson. The method is considered adequate to identify myocardial ischemia and has also been widely used in the identification of cardiac tumors. Progress has been made in the velocity of data acquisition, yielding perfusion images with high spatial and temporal resolution, as well as motion correction methods that positively contribute to the quality of the data.35^,39^-41 In a protocol for cardiac amyloidosis investigation, this sequence will be probably unnecessary, since a suspicion of myocardial ischemia is not considered for differential diagnosis in almost all cases.

Myocardial delayed enhancement is based on a T1-weighted fast gradient echo sequence, with an inversion recovery pre-pulse and inversion time (TI) adjusted to null the normal myocardial signal after infusion of gadolinium-based contrast (0.02 - 0.04 mmol/kg). Gadolinium does not penetrate intact cell membranes and hence is distributed in the extracellular space; in case of myocyte membrane rupture (e.g., infarction), gadolinium shows a larger volume of distribution.41^,42 In addition, kinetics of the contrast distribution is altered, with a slower washout.40

Consequently, gadolinium concentrations are much higher in regions of greater extracellular volume, and areas of membrane rupture and communication between intra and extracellular space as compared with normal myocardial tissue approximately 10 minutes after the contrast administration.39 These areas are white in delayed enhancement images (hypersignal), whereas normal myocardium appears black (low signal - null).

Recent technological progresses have allowed acquisition of three-dimensional late gadolinium enhancement, with respiratory navigator during free breathing, one respiratory pause, in real time and without manual adjustment of TI (self-viability or phase sensitivity inversion recovery - PSIR - technique).7^,35

Therefore, in cardiac amyloidosis, tissue definition after contrast administration is obtained from gadolinium deposition and accumulation in areas with increased myocardial extracellular volume. Such increase in extracellular space results from expansion of amyloid deposits to the extracellular space. Several studies using the delayed enhancement technique have enabled the classification of amyloid deposition patterns - subendocardial (Figure 3), mesocardial (Figure 4) and transmural (Figure 5).15 The most common patterns of amyloid distribution in immunoglobulin light chain amyloidosis and transthyretin amyloidosis are subendocardial and transmural, respectively.43 The treatment of amyloidosis depends on the disease subtype; the use of delayed enhancement CMR is hence paramount as it serves as a screening test that lead to other test, such as biopsy, for establishment of disease subtype and definition of therapy.

Figure 3

Figure 4

Figure 5

Thus, it is important to reinforce that CMR with late enhancement can be used not only for the diagnosis of cardiac amyloidosis, but also can influence the type of therapy and follow-up of patients, and hence be decisive for the prognosis of these individuals.

An important advance in cardiac amyloidosis treatment is the increasing use of quantitative analysis by magnetic resonance, including measurements of the T2 (edema) and T2* (iron deposition) and T1 mapping, focusing on non-invasive quantification of diffuse myocardial fibrosis. The most used sequence for T1 mapping quantification is the modified lock-locker inversion recovery (MOLLI) (Figure 6).44^-51

Figure 6

With technological advances in the context of amyloidosis or even infiltrative diseases, the use of ECV expansion and T1 mapping has been consolidated in the diagnosis and follow-up of patients with myocardial interstitial disease caused by increased amyloid deposition or fibrosis. T1 mapping transforms a physical principle of magnetic resonance into a quantifiable number (expressed in milliseconds) in an image. T1 relaxation time is the measure of how quickly the longitudinal magnetization component recovers to its equilibrium state. In the T1 mapping technique, measurements of T1 relaxation with and without contrast can be obtained by a simple software that directly defines a region of interest within the myocardium, generating pre- and post-contrast administration values in milliseconds. Amyloid deposition increases T1 in the pre-contrast phase and reduces T1 in the post-contrast phase due to increased extracellular space by the amyloid infiltration.44^-51

It has demonstrated that T1 mapping without contrast can identify amyloid deposits with a T1 of approximately 1,140 ± 61 ms.29 In post-contrast studies, the cut-off value demonstrated to have a worse prognosis was 565 ms when combined with a pre-contrast value greater than 1,044 ms.52

In addition, the use of pre- and post-contrast T1 mapping enables the calculation of the ECV fraction by the relationship between relaxation fractions of the cardiac muscle and the blood, corrected by hematocrit:

Δ R 1 myocardium / Δ R 1 blood * 1 − Ht

Normal ECV in healthy volunteers is 27 ± 3%.46^,49

These made the assessment of interstitial fibrosis or subclinical amyloid deposition by T1 mapping possible, even in situations of negative delayed enhancement magnetic resonance imaging. T1 time is decreased in the presence of fibrosis (Figure 7), making this map and powerful tool for quantification of ECV expansion and fibrosis. T1 mapping has been validated by endomyocardial biopsies in patients with non-ischemic heart diseases, referred for cardiac transplantation.51 The measurement of the ECV fraction determines, in percentage, areas of possible fibrosis not yet detected by delayed enhancement technique.52^-54

Figure 7