Summary
Amyloidosis is a severe systemic disease. Cardiac involvement may occur in the three main types of amyloidosis (acquired monoclonal light-chain, hereditary transthyretin and senile amyloidosis) and has a major impact on prognosis. Imaging the heart to characterize and detect early cardiac involvement is one of the major aims in the assessment of this disease. Electrocardiography and transthoracic echocardiography are important diagnostic and prognostic tools in patients with cardiac involvement. Cardiac magnetic resonance imaging better characterizes myocardial involvement, functional abnormalities and amyloid deposition due to its high spatial resolution. Nuclear imaging has a role in the diagnosis of transthyretin amyloid cardiomyopathy. Cardiac biomarkers are now used for risk stratification and staging of patients with light-chain systemic amyloidosis. Different types of cardiac complications may occur, including diastolic followed by systolic heart failure, atrial and/or ventricular arrhythmias, conduction disturbances, embolic events and sometimes sudden death. Senile amyloid and hereditary transthyretin amyloid cardiomyopathy have better prognoses than light-chain amyloidosis. Cardiac treatment of heart failure is usually ineffective and is often poorly tolerated because of its hypotensive and bradycardiac effects. The three main types of amyloid disease, despite their similar cardiac appearance, have specific new aetiological treatments that may change the prognosis of this disease. Cardiologists should be aware of this disease to allow early treatment.
Résumé
L’amylose est une maladie systémique grave. Les 3 principaux types d’amylose avec atteinte cardiaque sont l’amylose à chaînes légères, l’amylose héréditaire à transthyrétine et l’amylose sénile à transthyrétine non mutée. L’atteinte cardiaque conditionne le pronostic dans ces 3 formes. L’électrocardiogramme et l’échographie cardiaque sont indispensables pour le diagnostic et l’évaluation du risque de ces patients. Les biomarqueurs cardiaques sont utilisés depuis quelques années pour la stratification du risque en particulier dans l’amylose à chaînes légères. L’IRM cardiaque est de plus en plus utilisée pour évaluer ces patients mais son rôle n’est pas encore bien défini. L’imagerie nucléaire est intéressante chez les patients avec suspicion d’amylose à transthyrétine. Les complications cardiaques peuvent être principalement hémodynamiques (dysfonction diastolique puis systolique), ou électriques (arythmies atriales ou ventriculaires malignes; BAV de différents degrés), avec risque de mort subite. Le pronostic de l’amylose à transthyrétine héréditaire ou sénile est meilleur que celui des amyloses à chaînes légères. Malgré une certaine similarité dans la présentation clinique et l’imagerie, un traitement étiologique spécifique existe pour chaque type d’amylose systémique, dont il peut modifier le pronostic. En raison de l’atteinte cardiaque fréquente, les cardiologues devraient être sensibilisés au diagnostic rapide de cette maladie afin qu’un traitement précoce puisse être institué.
Introduction
Amyloidosis is due to extracellular tissue deposition of insoluble fibrils composed of a variety of serum proteins (amyloid), resulting in tissue involvement. Deposition of amyloid can be localized or systemic (in virtually all organs except the brain). Clinical manifestations are based on the site of the amyloid deposits and are related to the type of precursor protein involved.
There are many types of precursors that may affect the heart: light-chain (LC) immunoglobulin, mutant hereditary transthyretin (TTR), wild-type TTR, mutant apolipoprotein AI, amyloid atrial natriuretic peptide localized to the atrium, fibrinogen alpha type and serum amyloid A protein. Secondary amyloidosis is typically a consequence of chronic inflammatory conditions, such as rheumatoid arthritis , Crohn’s disease or other chronic inflammatory/infectious diseases, familial Mediterranean fever or idiopathic amyloid A amyloidosis .
The organs involved are typically the liver, kidney, gastrointestinal tract, nervous tissue and heart. The presence of amyloid deposits in the heart varies with the type of amyloidosis: systemic senile amyloidosis (SSA) and some forms of hereditary TTR-related amyloidosis (ATTR) affect the heart almost invariably, whereas cardiac involvement in LC amyloidosis (AL) is present in about 50% of cases. In secondary amyloidosis, cardiac involvement is rare or minimal or clinically non-significant .
The present review focuses on the three main types of systemic amyloidosis (AL, ATTR and SSA) and describes cardiac involvement.
Light-chain amyloidosis
AL is not rare, with a reported incidence in USA of 8.9 per million person-years, and is probably underdiagnosed . The estimated incidence of AL in France is roughly 500 patients per year. AL is caused by the extracellular deposition of fibril-forming monoclonal immunoglobulin LCs, usually secreted by a small plasma cell clone. The fibrils consist of monoclonal kappa or lambda LCs . A serum and/or urine monoclonal component is detectable by immunofixation and/or immunoelectrophoresis in 80–90% of patients. With the use of sensitive techniques, such as nephelemetric measurement of serum free LCs, an abnormal concentration of serum free LCs is found in > 90% of patients, with an over-representation of the lambda isotype compared with the kappa isotype . Plasmocytosis is present in the bone marrow in > 50% of patients.
The diagnosis of AL is always based on histological findings using light microscopic examination, showing amorphous extracellular Congo red positive deposits ( Fig. 1 A), which display characteristic dichroism and apple green birefringence under polarized light ( Fig. 1 B) Non-invasive biopsies of abdominal fat and minor salivary glands should be performed initially; the latter biopsy is usually positive in 80% of patients. If necessary, i.e. when tissue biopsies fail to demonstrate amyloid deposition, biopsy of a clinically affected organ (kidney, gastrointestinal tract or endomyocardial tissue) should be considered. Electron microscopy may be useful to confirm the presence of amyloid deposits, which typically display the ultrastructural appearance of randomly arranged fibrils ( Fig. 2 ), 7–10 nm in external diameter. Immunohistological typing is indispensable to make the differential diagnosis between different types of amyloid disease (AL versus ATTR wild-type, mutant or with other precursors).
Diagnostic criteria for cardiac involvement
Cardiac involvement is one of the most frequent types of solid organ manifestation . In patients with cardiac involvement, the lambda LC isotype is the most frequent and is observed in 70% of cases.
Since 2005, organ involvement in systemic AL has been defined by consensus criteria , which were updated at the 2010 meeting of the International Society of Amyloidosis in Rome. Cardiac involvement is characterized by an increase in mean wall thickness in end-ventricular diastole of ≥ 12 mm by echocardiography, with no other obvious cardiac cause, associated with an increase in the concentration of N -terminal prohormone of B-type natriuretic peptide (NT-proBNP) to > 332 ng/L (in absence of renal failure).
Cardiac biomarkers
NT-proBNP and cardiac troponin have been used widely since 2004 for assessing cardiac involvement severity and prognosis in AL and a current staging system–the Mayo Clinic staging–has been established, based on NT-proBNP (cut-off value = 332 ng/L; BNP = 100 ng/L) and cardiac troponin (cut-off value = 0.035 μg/L), in order to stratify patients into three groups:
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high risk (stage III: both biomarkers are increased);
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intermediate risk (stage II: at least one biomarker is above the cut-off value);
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low risk (stage I: both biomarkers are below the cut-off values).
This Mayo Clinic staging is now used by the medical community before the choice of therapy is made.
Recently, ultrasensitive troponin has emerged as a more sensitive biomarker of cardiac injury; thus, another classification has been proposed by Kristen et al. , using the same cut-off value for NT-proBNP and a cut-off value of 50 ng/L for ultrasensitive troponin.
Another biomarker – midregional proadrenomedullin, which is produced by many organs, including the heart – was tested in an Italian study in 2011 , in 130 patients with confirmed de novo AL. The authors found that a high concentration of midregional proadrenomedullin was associated with a higher early mortality rate of 40% at 6 months when its value was > 0.75 nmol/L.
Electric disturbances
Electrocardiograms (ECGs) are abnormal in 90% of cases with cardiac involvement. The largest study that reported ECG findings consisted of 127 patients with AL and biopsy-proven cardiac involvement seen at the Mayo Clinic . The study confirmed that the two most common abnormalities were low voltage QRS complex (defined as all limb leads < 5 mm in height) and a pseudoinfarct pattern on the precordial leads ( Fig. 2 ), which were seen in roughly 50% of the patients included. Right and left bundle branch block are uncommon. Other changes that may occur include conduction abnormalities (such as second and third degree atrioventricular block), more frequently atrial fibrillation in about 15% of patients and, rarely, ventricular tachycardia in about 5% of patients. A recent study that included a large number of patients with AL with and without cardiac involvement, reported that a fragmented QRS (notches and RsR’ pattern in the absence of QRS prolongation) was significantly more frequent in patients with cardiac amyloidosis (28.5% vs. 11.7%; P = 0.0008). Moreover, the group with fragmented QRS had a significantly higher mortality rate compared with the ‘normal’ QRS group ( P = 0.0008). According to the authors, fragmented QRS had a prognostic value independent of QRS duration, QTc interval, NT-proBNP serum concentration and LV wall thickness. However, these ECG findings are not specific to cardiac amyloidosis and any severe cardiomyopathy with severe myocardial injury may be responsible for a fragmented ECG, irrespective of its aetiology.
Twenty-four-hour Holter ECG monitoring might help to identify asymptomatic ventricular/supraventricular arrhythmias in > 75% of cardiac AL patients. Complex ventricular arrhythmias have been reported to be prognostic determinants for survival, but only couplets correlated with sudden cardiac death and were independent predictors of survival . A 24-hour Holter ECG may also show the absence of heart rate variability due to autonomic dysfunction, which is frequent in cardiac amyloidosis .
Regarding endocavitary conduction disturbance, a large study that included patients with confirmed AL found that they all had normal sinus function. However, the infra-Hisian conduction time was significantly prolonged (79 ms) and was independently associated with the occurrence of sudden death; the authors concluded that HV prolongation may be a marker of significant infiltration of myocardium by amyloid fibrils, which may be responsible not only for ventricular tachycardia, but also for severe atrioventricular conduction abnormalities with high degree atrioventricular block or asystole.
Echocardiographical findings
Cardiac involvement is usually characterized by the presence of an infiltrative/restrictive cardiomyopathy with classical echocardiographical findings, which have been well described , but also by new echocardiographical findings identified using strain imaging.
Transthoracic echocardiography (TTE) ( Fig. 3 A) typically shows the following features:
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increased LV wall thickness ≥ 12 mm with ‘brilliant’ speckled appearance of the myocardium (amyloid fibrils deposits are more echogenic than normal myocardium); a mean LV wall thickness > 15 mm was independently associated with worse outcome ;
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normal or small LV cavity;
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preserved LV ejection fraction (LVEF) > 50% (at least in the early stage of the disease), but reduced S and E’ waves at the basal, septal or lateral myocardium level, reflecting the poor longitudinal function and altered LV relaxation;
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abnormal mitral filling pattern, due to mild or moderate LV diastolic dysfunction (type I mitral or pseudonormalized pattern); and at a later stage, a typical severe restrictive mitral filling pattern with E/A ratio > 2, increased E/E’ and small A wave due to atrial dysfunction;
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the elevated LV filling pressure may lead progressively to left atrial enlargement (diameter > 23 mm/m 2 , area > 20 cm 2 or maximal volume > 28 mL/m 2 ), which seems not only to be helpful for differential diagnosis , but also to be independently associated with worse outcome in AL ;
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right atrial enlargement and dilated vena cave reflecting right ventricular (RV) filling pressure;
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increased interatrial septal thickness (it must be emphasized that this variable is much easier to measure by cardiac magnetic resonance imaging [cMRI] than by echocardiography);
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increased RV free wall thickness (> 7 mm) with RV systolic and diastolic dysfunctions associated with worse survival ;
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left and right valve thickening, usually responsible for mild regurgitation;
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reduced aortic ejection time (< 273 ms), described as a prognostic factor ;
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small pericardial effusion in 50% of cases, the presence of which is independently associated with worse survival ; exceptionally, an aspect of large pericardial effusion with tamponade may reveal the systemic disease ;
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atrial thrombi may be seen, despite the presence of sinus rhythm; one large study that analysed the presence of atrial thrombi in patients with confirmed AL found that AL patients were younger and had less atrial fibrillation than those with other types of amyloidosis; however, the AL group had significantly more intracardiac thrombi (51% vs. 16%; P < 0.001) and more fatal embolic events (26% vs. 8%; P < 0.03).
Diagnostic and prognostic value of new echocardiographical techniques
A large study recently published by Buss et al. , which included 200 consecutive patients with AL with systematic assessment of LV longitudinal function, showed that: longitudinal strain (LS) and 2D global LS (2D-GLS) were strongly correlated with NT-proBNP in patients with AL; reductions in LS and 2D-GLS were both independently associated with prognosis in AL, including overall survival, compared with standard TTE variables; and LS and 2D-GLS provided incremental value over NT-proBNP, cardiac troponin and all other clinical variables assessed.
Another recent study was designed to show the diagnostic importance of two-dimensional speckle-tracking imaging in differentiating cardiac amyloidosis from other causes of LV hypertrophy. Using 55 patients with confirmed AL, the authors found that the amyloid heart is characterized by reduced basal strain and regional variations in LS from base to apex ( Fig. 3 B), and that a relative ‘apical sparing’ (average apical LS/[average basal LS + mid-LS]) pattern of LS is an easily recognizable, accurate and reproducible means of differentiating cardiac amyloidosis from other causes of LV hypertrophy.
Therefore, this technique appears useful not only for diagnosis but also for the independent assessment of prognosis in patients with AL.
Cardiac magnetic resonance imaging
cMRI is often performed when cardiac amyloidosis is suspected because it has an excellent spatial resolution for tissue characterization and is very sensitive for detecting the presence of infiltrative cardiomyopathy, even in cases of normal LV wall thickness.
cMRI allows precise measurement of the LV walls, the interatrial and RV free walls, biatrial enlargement and pericardial effusion ( Fig. 4 ). cMRI is also useful for tissue characterization of the myocardium , by showing different patterns: transmural late gadolinium enhancement (LGE) or, more typically, a large diffuse annular LGE; less often a global heterogeneous LGE or rarely diffuse LGE, called ‘patchy LGE’. Indeed, gadolinium has an interstitial distribution, and in patients with cardiac amyloidosis there is an increase in interstitial cardiac volume because normal myocardium is replaced by amyloid fibrils. Thus, gadolinium stays longer in the tissue, which explains the late gadolinium enhancement.
