AL (Light-Chain) Cardiac Amyloidosis Review

Sep 16, 2016 |Ragavendra R. Baliga, M.B.B.S., FACC

Authors:

Falk R, Alexander KM, Liao R, Dorbala S.

Citation:

AL (Light-Chain) Cardiac Amyloidosis: A Review of

Diagnosis and Therapy.
2016;68:1323-1341.

The following are key points to remember from this review about current
approaches to the diagnosis and treatment of cardiac amyloidosis:
1. The most common forms of amyloid that a ect the heart are immunoglobulinderived light chains and transthyretin (TTR, previously called prealbumin).
There is a slight male predominance of AL (light-chain) cardiac amyloidosis,

and the disease generally presents from the fth to seventh decade, although
it may occur at all ages from the fourth decade onward. The median survival
from onset of heart failure (HF) is about 6 months in untreated patients, but
therapies can put the disease into a prolonged remission and extend life by
many years.
2. It is estimated that AL amyloidosis is approximately one-tenth as common as
multiple myeloma, with an estimated annual age-adjusted incidence in the
United States of 10.5 cases per million person-years. Approximately 5-10% of
patients with AL amyloidosis will have evidence of overt multiple myeloma, and
a similar proportion of multiple myeloma patients will have AL amyloidosis. In
myeloma, amyloid in ltration of the heart is required before light-chain
cardiotoxicity can be clinically manifest.
3. AL amyloidosis, is a multi-organ disorder wherein renal, neural, and/or
dermatologic involvement often coexists with heart involvement. It most
commonly a ects the kidney, resulting in nephrotic syndrome, with clinical
cardiac involvement being the second most common presenting manifestation.
Less commonly, symptomatic hepatic and gastrointestinal in ltration may
occur. Other organ systems that may be involved include the peripheral and
autonomic nervous system, the vasculature, and the soft tissues. Cerebral
involvement does not occur in AL amyloidosis.
4. The severity of HF in AL amyloidosis was more severe than in TTR amyloidosis,
despite greater left ventricular (LV) mass in the latterthe authors provide

evidence suggesting that amyloid brils may have both toxic and in ltrative
components.
5. The most common early manifestation of cardiac amyloidosis of any type is
exertional dyspnea on exertion (which is due to LV diastolic dysfunction), which
progresses relatively rapidly, and is often followed by peripheral edema and
ascites. Peripheral edema in AL amyloidosis may also be due to
hypoalbuminemia associated with amyloid-related nephrotic syndrome, and
proteinuria should always be sought. However, the atria, although they do
dilate, are also abnormally sti , and prominent V waves may be seen in the
pulmonary capillary wedge tracings in the absence of signi cant mitral
regurgitation, and likely contribute to dyspnea on exertion. Atrial arrhythmia
may be the initial manifestation of the disease; surprisingly, this is relatively
uncommon as a presenting feature, particularly in AL amyloidosis. Exertional
syncope, most likely due to a low and xed cardiac output, can occur, and this
has a particularly poor prognosis.
6. Thromboembolism may thus be an early manifestation of the disease, and
unless the clinician is aware of the phenomenon of left atrial systolic
dysfunction, the source of neurological or systemic embolism may not be
recognized.
7. The signs of the noncardiac disease are commonly present. Approximately
10% of patients have macroglossia, which may vary from very obvious tongue
enlargement to subtle tooth indentation of the tongue. Periorbital bruising in

the setting of HF is almost pathognomonic of light-chain amyloidosis; as it may

be subtle, the eyelids should be inspected for small bruises. Hepatomegaly
usually re ects congestion, but an enlarged liver may also be due to amyloid
in ltration in patients with AL amyloidosis.
8. Unlike severe HF caused by most other etiologies, a third heart sound is
uncommon in cardiac amyloidosis, as is a fourth heart sound. Valvular
dysfunction due to amyloidosis is rarely severe, other than, on occasion,
tricuspid regurgitation.
9. Electrocardiography (ECG) typically shows low-voltage QRS complexes, but the
P-wave is usually of normal voltage, but frequently abnormal in morphology,
and is often markedly prolonged, representing slowed atrial conduction due to
amyloid in ltration. Low-voltage ECG often precedes HF, and may be present
before an increase in LV wall thickness is apparent on echocardiogram. This is
an early marker of the disease. Low-voltage QRS complexes are far less
common in ATTR than in AL amyloidosis, despite a greater amyloid burden in
the heart.
10. The echocardiogram typically shows concentric LV thickening, often with right
ventricular (RV) thickening. The LV wall may be more echogenic than in true LV
hypertrophy, and, due to the extensive amyloid deposits, LV wall thickness
frequently equals or exceeds 15 mm. A wall thickness >18 mm can be seen in
AL amyloidosis, but is more common in ATTR. It is unusual for hypertensive
heart disease to have LV walls >15 mm, unless hypertension is severe,

longstanding, and persistent, and the discrepancy between increased LV mass

on echocardiogram and low voltage on ECG should increase suspicion of
cardiac amyloidosis. There may be both loss of reservoir function (absence of
atrial expansion during ventricular systole) and loss of contractile function
(absence of atrial contraction during late ventricular diastole).
11. Cardiac magnetic resonance (CMR) imaging shows two main features. These
include the di culty in nulling the myocardium following gadolinium injection
and a noncoronary, usually subendocardial, pattern of delayed gadolinium
enhancement, both within the ventricular myocardium and in the atrium.
12. The sine qua non of diagnosis, in patients with evidence of monoclonal
gammopathy, is tissue biopsy showing amyloid deposits.
13. Therapy of AL cardiac amyloidosis is two-fold: optimal treatment of HF and
chemotherapy aimed at abolishing the amyloidogenic plasma cell dyscrasia.
Diuretic agents (a loop diuretic with spironolactone) are the mainstay of HF
therapy, as angiotensin-converting enzyme inhibitors and angiotensin-receptor
blockers are poorly tolerated due to hypotension. Beta-blockers may also
aggravate hypotension and are usually avoided (they may be used cautiously
in selected patients with atrial brillation and a rapid ventricular response).
Calcium-channel blockers often signi cantly worsen congestive HF. Digoxin
appears to o er no bene t in HF due to amyloid cardiomyopathy, and digoxin
toxicity with therapeutic digoxin levels may occur because of altered binding
properties.

14. Even when the patient is in sinus rhythm, anticoagulation should be

administered if the echocardiogram shows features of left atrial mechanical
dysfunction, as thrombus formation and thromboembolism may occur in these
patients.
15. In the authors' experience, amiodarone and dofetilide are well tolerated for
atrial arrhythmias. Nonsustained ventricular arrhythmias are uncommon in
such patients and sudden death, if it occurs, is most commonly due to sudden
profound bradycardia or pulseless electrical activity. There is no proven bene t
of either prophylactic pacing or prophylactic implantable de brillator in these
patients.
16. Proteosome-inhibiting agents, speci cally bortezomib, have considerably
improved the prognosis of patients with AL cardiac amyloidosis. Bortezomib is
relatively well-tolerated, even in the presence of amyloid cardiomyopathy, and
is usually combined with dexamethasone, frequently with low-dose
cyclophosphamide.
17. High-dose chemotherapy with autologous stem-cell transplantation is generally
reserved for suitable cardiac amyloidosis patients who have failed to fully
respond to oral regimens, and may produce a complete hematologic response.
Stem cell collection is often associated with uid retention and hypotension,
and atrial arrhythmias may occur following chemotherapy. Generally,
hypotension is well-tolerated, and the temptation to treat with intravenous
uids should be avoided in the asymptomatic patient.

18. Cardiac transplantation in AL amyloidosis has been performed, but the

outcome depends on extremely careful selection of patients. One-year overall
survival was 64% after LV assist device (LVAD) implantation, with no di erence
between amyloidosis and non-amyloidosis patients, but with a very poor
survival if the LV end-diastolic dimension was <46 mm.
19. A promising therapeutic option appears to be a two-pronged approach of
depletion of circulating Serum amyloid P component (SAP) followed by the
administration of a fully humanized immunoglobulin-1 anti-SAP monoclonal
antibody to target the SAP on the amyloid brils.
Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Cardio-Oncology,
Geriatric Cardiology, Heart Failure and Cardiomyopathies, Invasive
Cardiovascular Angiography and Intervention, Prevention, Valvular Heart
Disease, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial
Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias,
Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Acute Heart
Failure, Heart Transplant, Interventions and Structural Heart Disease,
Interventions and Vascular Medicine, Hypertension, Mitral Regurgitation
Keywords: Amyloid, Amyloidosis, Arrhythmias, Cardiac, Atrial Fibrillation, Cardiac Surgical
Procedures, Cardiomyopathies, Cardiotoxicity, Cell Transplantation, Dyspnea, Edema,
Electrocardiography, Embolism, Gadolinium, Geriatrics, Heart Failure, Heart Transplantation,
Hepatomegaly, Hypertension, Hypotension, Immunoglobulin Light Chains, Mitral Valve
Insu ciency, Multiple Myeloma, Myocardium, Nephrotic Syndrome, Plaque, Amyloid,

Proteinuria, Spironolactone, Syncope, Systole, Thromboembolism, Thrombosis, Tricuspid Valve

Insu ciency

2016 American College of Cardiology Foundation. All rights reserved.