Author’s Accepted Manuscript

Cardiac Amyloidosis- An Updated Review with

Emphasis on Diagnosis and Future Directions

Sukhdeep Bhogal, Vatsal Ladia, Puja Sitwala,

Emilie Cook, Kailash Bajaj, Vijay Ramu, Carl J.
Lavie, Timir K. Paul
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PII: S0146-2806(17)30070-1
DOI: http://dx.doi.org/10.1016/j.cpcardiol.2017.04.003
Reference: YMCD345
To appear in: Current Problems in Cardiology
Cite this article as: Sukhdeep Bhogal, Vatsal Ladia, Puja Sitwala, Emilie Cook,
Kailash Bajaj, Vijay Ramu, Carl J. Lavie and Timir K. Paul, Cardiac
Amyloidosis- An Updated Review with Emphasis on Diagnosis and Future
D i r e c t i o n s , Current Problems in Cardiology,
http://dx.doi.org/10.1016/j.cpcardiol.2017.04.003
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Cardiac Amyloidosis- An Updated Review with Emphasis on
Diagnosis and Future Directions
Authors

Sukhdeep Bhogal1, Vatsal Ladia2, Puja Sitwala2, Emilie Cook3, Kailash Bajaj1, Vijay Ramu2, Carl J.
Lavie,4 Timir K Paul2

Affiliations

Department of Internal Medicine, East Tennessee State University1

Division of Cardiology, East Tennessee State University2

Department of Pathology, East Tennessee State University, Johnson City, TN, USA 3

Department of Cardiology, Oschsner Clinical School-the University of Queensland School of

Medicine, New Orleans, LA, USA4

Corresponding author:

Timir K Paul, MD, PhD

329 N State of Franklin Rd
Johnson City, TN 37604
Phone: 423-979-4100
Fax: 423-979-4134
Email: pault@etsu.edu

Conflict of interest- None

Abstract
Cardiac amyloidosis occurs as a result of abnormal protein (amyloid) deposition in the cardiac
tissue. Even with advanced diagnostic techniques and treatments, the prognosis of amyloidosis
remains poor. The diagnosis of cardiac amyloidosis particularly needs to be in the differential in
patients presenting with heart failure with preserved ejection fraction. This entity remains
underdiagnosed due to lack of suspicion on the part of many clinicians. Involvement is cardiac
tissue is the utmost determinant factor for available treatment options and prognosis. Many
cases of cardiac amyloidosis usually remain undiagnosed or diagnosed only in advanced stages
when treatment options are limited and associated with poor survival. Hence, early recognition
of cardiac amyloidosis is indispensable in halting the disease process before irreversible
changes occurs. The purpose of this review is to summarize the recent updates in the
evaluation and management of cardiac amyloidosis and discuss potential future treatments
options.

Introduction
Amyloid is defined as the extracellular tissue deposition of amyloid fibrils which are comprised
of low molecular weight subunit proteins. Cardiac amyloidosis in one of the common infiltrative
cardiomyopathies associated with an unfavorable prognosis. The pathophysiology involves the
adoption of normal protein into an amyloid state, resulting from cleavage, denaturation or
excess production of abnormal protein, 1 which eventually assume antiparallel beta-pleated
sheet configuration forming amyloid fibrils. Clinical outcome depends on the extent of tissue
involvement and the type of amyloid fibril deposits.

Types of Amyloidosis
The major subtypes of systemic amyloidosis classified based on the underlying etiologies are:
Primary (AL) amyloidosis, Secondary (AA) amyloidosis (or reactive amyloidosis), Familial
amyloidosis (ATTR or hereditary amyloidosis), Dialysis related amyloidosis and Senile systemic
amyloidosis (SSA; Table 1). Of these, AL, ATTR and SSA commonly involve the myocardium.
However, AA rarely impacts the cardiac function.

Primary Amyloidosis
Being a relatively rare but rapidly progressive disease, the amyloid fibrils in AL are composed of
monoclonal light chains and is usually associated with plasma cell disorders, such as multiple
myeloma or other B cell dyscrasias. Cardiac involvement is common in primary amyloidosis and
is a crucial factor for determining the clinical prognosis. Mortality is high when cardiac
involvement is present and prognosis remains poor.

Familial or Hereditary Amyloidosis

Transthyretin, also called TTR or preablumin gene, is located on the long arm of chromosome
18, and more than 120 TTR mutations have been described in the literature, and almost all of
them are found to be amyloidogenic. Mutations could be at a single location, compound
mutations or deletions 2 and manifest as an autosomal dominant pattern of inheritance. Most
patients with ATTR have heterozygous mutations of TTR. While non-cardiac manifestations,
such as polyneuropathy, ocular infiltration, alteration of autonomic function are present with
some TTR mutations in European or Japanese populations, cardiac manifestations are
frequently noted in United States (US) populations, more commonly in African Americans and
frequently result from mutations causing substitution of isoleucine for valine at 122 position
(Val 122l1e mutation) 3, which is the most frequent mutation present in the US.

Senile Systemic Amyloidosis

Also known as wild type transthyretin (TTRwt), a transport protein synthesized by liver, SSA
usually involves male populations predominantly more than 70 years of age. Other tissues
infiltrated by this amyloidogenic protein are pancreas, brain, kidneys, and lungs. This disease is
less aggressive than AL because of slower rate of disease progression. After suspicion,
endomyocardial biopsy is required due to isolated cardiac involvement in most cases; SSA is the
diagnosis of exclusion after ruling out AL and ATTR 4.
 Types Primary Light chain Familial amyloidosis Senile cardiac
amyloidosis amyloidosis

5 5 5
Nomenclature AL ATTR SSA or ATTRwt
Epidemiology Exact incidence is 3.5 -4 % of African- 1-2% in blacks and 0.4%
8
unknown, estimated Americans in US with Val in non-Hispanic whites
7
incidence is 6-10 cases 122lle mutation
per 1,000,000 population
6

Age Median age 60-75 years, Variable according to Predominantly males,

6 3,
>60 % cases are men mutations, Val122l1e age more than 70 years
4
mutation almost always
3
more than 60 years
9 5
Protein involved Monoclonal light chain Variants of transthyretin Wild type Transthyretin
2
with >120 mutations
Cardiac features HFpEF, atrial/ventricular HFpEF, atrial/ventricular HFpEF, atrial/ventricular
arrhythmias and arrhythmias and arrhythmias and
first/second degree or first/second degree or first/second degree or
9 3 4
advanced heart block advanced heart block advanced heart block
Extracardiac features Characteristic findings- Hepatomegaly, nephrotic Bilateral carpel tunnel
10, 11
Peri-orbital edema and syndrome, purpura, easy syndrome
macroglossia bruising, carpel tunnel,
Other findings- peripheral
3
Hepatomegaly, nephrotic polyneuropathy
syndrome, purpura, easy
bruising, carpel tunnel,
peripheral
9
polyneuropathy

Diagnostic modalities serum protein Technetium Diagnosis of exclusion,

electrophoresis, urine pyrophosphate, Genetic EMB (4,53)
protein electrophoresis, testing,
detection of serum free EMB (47,50,53)
light chains, EMB
(17,53)
Treatment Heart failure therapy, Heart failure therapy, Heart failure therapy,
chemotherapy, Heart chemotherapy, Isolated heart transplant,
transplant followed by orthotropic liver new novel agents (11,58-
autologous stem cell transplantation, 60,84)
transplant (22,58-60,63- combined liver and heart
73) transplant, new novel
agents (58-60,74-83)
HFpEF-Heart failure with preserved ejection fraction, EMB- Endomyocardial Biopsy

Table 1- Summarizes various types of amyloidosis with brief clinical features, diagnostic modalities and
treatment
Clinical Manifestation of Cardiac Amyloidosis
Symptoms
While systemic involvement of amyloidosis varies according to organ involvement, cardiac
manifestations predominantly include symptoms of right sided heart failure (HF). Infiltration of
amyloid fibrils results in stiffening and thickening of ventricles causing decreased compliance
and increased pressure altering the mechanics of ventricular function manifesting as diastolic
dysfunction (DD). Furthermore, cytotoxic effects of amyloid fibrils result in apoptotic and
fibrotic changes, thus eventually causing systolic function. This leads to presenting symptoms of
HF, such as dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, abdominal
distension and lower extremity edema.

Involvement of cardiac conduction system causes first degree, second degree or advanced
heart block or arrhythmias that can be symptomatic secondary to direct amyloid deposits in
conduction system or due to ischemia resulting from it 3. Syncope can be due to heart block or
arrhythmias and could be an indicator for poor survival outcome 12. Atrial fibrillation (AF) is the
most common arrhythmia described in approximately 10-20% of patients and heightens the risk
of thromboembolism 13. In one study, complex ventricular arrhythmias were seen almost in half
of the patients 14. Sudden cardiac death (SCD) can occur and is likely due to electromechanical
dissociation (EMD) instead of ventricular arrhythmias 12. Also, angina or infarction can occur in
patients with amyloid deposition in coronary arteries 15. Pleural and pericardial effusion is seen
with the advanced cardiac dysfunction. Regardless of type, cardiac amyloidosis generally
presents as restrictive cardiomyopathy with DD and eventually ensue biventricular systolic
dysfunction.

Physical Examination
Physical examination could be of high yield even though there is no pathognomonic finding or
sign. Patients could be completely asymptomatic or may present with various signs and
symptoms. Careful inspection may reveal elevated neck veins or elevated jugular venous
pressure (JVP). The apical beat is generally not shifted and could be barely palpable or
impalpable in advanced stages. Right sided S3 can be evident in advanced cases of right sided
ventricular dysfunction. Even though this is typically a restrictive cardiomyopathy resulting in
loss of relaxation function of ventricle, the fourth heart sound is an exceedingly rare finding
secondary to loss of atrial kick due to atrial amyloid infiltration 16. It also explains associated
finding of loss of a wave on JVP. Hypotension or resolving hypertension in previously
hypertensive patients could be seen as a result of low cardiac output. Orthostatic hypotension
may be present in patients secondary to autonomic neuropathy.
Extracardiac manifestations should also be examined carefully in suspicious cases, which may
include purpura, bruising, macroglossia or peri-orbital ecchymosis. Hepatomegaly and ascites
are seen in advanced cases of right heart HF. A history of bilateral carpel tunnel syndrome could
be an important clue for the patients suspected for SSA 10, 11. Nephrotic syndrome in AL and HF
or hypoalbuminemia secondary to liver failure in ATTR can lead to progressive lower extremity
edema. Painful neuropathy could be another nonspecific sign demanding additional work up in
suspected cases.

Diagnostic Modalities for Cardiac Amyloidosis

In suspected cases of cardiac amyloidosis, diagnostic approach is depicted in Figure 4 and 5.
Table 2 summarizes the characteristic findings, early diagnostic findings, sensitives and
specificity for various modalities for diagnosis of amyloidosis. Except for clinical findings,
laboratory and non-invasive tests are the main next steps in the diagnosis of amyloidosis.

Laboratory
As AL amyloidosis is mostly associated with plasma cell disorder, further evaluation should be
undertaken to detect paraproteinemia or monoclonal proteins, which include serum protein
electrophoresis (SPEP), urine protein electrophoresis (UPEP), immunofixation electrophoresis
and detection of serum free light chains. Serum free light chain is a quantitative test which can
detect light chains with higher sensitivity than immunofixation electrophoresis 17. It measures
the kappa to lambda ratio that ranges from 0.26 – 1.65 with ratio more than 1.65 suggesting
the abundance of kappa light chain and less than 0.26 the abundance of clonal lambda chains.
The presence renal failure results in decreasing the sensitivity from 81% to 60% 18. Serum free
light chain testing is usually done by freelite technique, which is currently the gold standard.
Recently, mass spectrometry, another evolving technique, can quantitatively measure the
monoclonal light chains and replaces the need for kappa to lambda ratio 19.

Role of B-Type Natriuretic Peptide

Local myocyte destruction along with wall stress results in elevated levels of troponins and B-
type natriuretic peptide (BNP) or N-terminal pro BNP (NT- pro BNP). If seen along with AL,
elevated BNP levels considered as a marker of cardiac involvement even before the onset of HF.
Although BNP levels are elevated in all causes of HF and are non-specific, but they do have
prognostic value in cardiac amyloidosis. In a Mayo clinic study 20, patients were categorized as
Mayo stage I, II and III based on the levels of following biomarkers; NT- proBNP (≥332 pg/ml)
and cardiac troponin T (≥0.035 ng/ml) or troponin I (≥ 0.1 ng/ml). Stage I patients had none,
stage II patients had either one of these and stage III patients had both aforementioned
findings. This study demonstrated median survival of 26, 11 and 4 months in stages I, II and III,
respectively, demonstrating their role as risk stratification in AL. Elevated NT-BNP is a sensitive
marker of cardiac infiltration and particularly levels more than 152 pmol/L are associated with
grim prognosis in AL 21. Also, serial measurement of NT-proBNP after chemotherapy is an
important tool to assess survival outcomes 22. Recently, new novel biomarkers, named as
soluble ST2 and galectin -3, serving as a marker of cardiac remodeling and fibrosis, has been
demonstrated to have prognostic value in HF, myocardial infarction and AL 23, 24.

There is no single noninvasive test pathognomonic of cardiac amyloidosis. Various modalities

such as the electrocardiogram (ECG), echocardiography (Echo), cardiac magnetic resonance
imaging (CMR), tissue biopsy and 99m-technetium pyrophosphate scanning (99mTc-PYP) are
being used to establish the diagnosis.

Electrocardiogram
The ECG is one of the easily available and cost effective modality that can provide invaluable
information regarding the underlying disease. Amyloid fibrils lead to deposition of completely
electrically silent material in the myocardium which is not detected by ECG. It results in low
voltage in limb leads (<5 mm) and poor R wave progression, also known as pseudoinfarction
pattern. This finding has been demonstrated in up to half of patients with AL 25. Furthermore,
these deposits also result in various arrhythmias, such as various heart blocks, AF and complex
ventricular tachycardia. The sum of amplitudes of S wave in V1 and R wave in V5 or V6 26 more
than 3.5 mV is considered as a measure of left ventricular hypertrophy (LVH) and less than 1.5
mV are found to be associated with dismal outcomes in all three types of amyloidosis with
cardiac involvement 27. The concentric LVH along with low voltage on the ECG is suspicious for
amyloidosis but it does not hold a sequential relationship with it 28. Also, combined R wave
voltage in I and aVR has better sensitivity and specificity of almost around 90% for
distinguishing amyloidosis from nonobstructive hypertrophic cardiomyopathy 29.
Echocardiogram
The Echo is recommended in all patients with suspected amyloidosis, and findings include
biatrial enlargement, thickening of ventricular wall and/or valves, decreased diastolic filling and
classic granular sparkling appearance. However, none of these findings are specific for
diagnosing amyloidosis. It is important to individually correlate the findings based on the clinical
presentation and case suspicion. For example, thickened left ventricular wall in patients
without history of hypertension is peculiarly suspicious. The wall thickness is attributed to
infiltrative amyloid deposition instead of myocytes hypertrophy 30. Frequently, DD, particularly
the abnormal relaxation of the ventricle, is seen in early stages 31. If remain undiagnosed, DD
worsens and reaches to a point where systolic dysfunction ensues. Decreased left ventricular
ejection fraction (LVEF) is of grim prognostic significance 32. Recently, myocardial contraction
fraction, computed by dividing stroke volume to myocardial volume, is found to exhibit better
prognostic value as compared to LVEF 33. Doppler Imaging has particularly revolutionized the
world of cardiac imaging in terms of assessing cardiac amyloidosis. Doppler measurements
include the assessment of ratio (E/A) of early (E) and late (A) diastolic peak velocities along with
deceleration time (time taken by peak E velocity to return to baseline). Klein et al has
demonstrated that findings such as short deceleration time and increased early diastolic filling
velocity to atrial filling velocity has prognostic significance for mortality assessment 31.
Assessing strain and strain rate (longitudinal axis dysfunction) using Doppler can reveal cardiac
amyloidosis in its subclinical stages 34 and is helpful in determining the survival outcomes. With
advances in imaging techniques, development of speckle tracking echo, overcoming the
limitation of Doppler imaging, is a much better tool for analyzing the longitudinal axis,
particularly radial and circumferential strain. The significant decrease of longitudinal strain in
the mid and basal-wall regions with relative preservation of the apical region have been found
to be diagnostic findings in patients of cardiac amyloidosis with high sensitivity and specificity
ranges from 90-95% and 80-85%, respectively 35. Nevertheless, even with advancement in
technologies, there are no specific findings that can be used to diagnose amyloidosis based on
echo alone.

Cardiac Magnetic Resonance Imaging

Recently, CMR is an important diagnostic and prognostic tool in the assessment of severity of
cardiac amyloidosis. Various techniques are currently used and include strain analysis and
tissue imaging with contrast and without contrast.

Strain analysis based on CMR can be accomplished with the recent advances, a technique
known as Displacement Encoding with Stimulated Echoes with high sensitivity and specificity
close to echo 36. Though not extensively studied in amyloidosis patients, it is a highly precise
modality and hold promises in generation of strain time curves with “tissue tracking”
techniques. In contrast, CMR is the most studied technique for diagnosis of amyloidosis. Injury
to the myocardium secondary to deposition of amyloid fibrils in interstitium serves as a
reservoir for gadolinium accumulation leading to characteristic late gadolinium enhancement
(LGE) 37 (Figure1). This technique has a sensitivity of close to 80% and impressive specificity of
94% 38. Syed et al has demonstrated that global transmural or diffuse subendocardial LGE could
be invaluable to detect amyloidosis in early phase even before the onset of left ventricular wall
thickening and has correlation with the severity of disease 39. Recently, another study showed
that transmural LGE is more prevalent in ATTR (97%) as compared to AL patients (37%) 40.
However, LGE imaging poses some limitations in terms of a) diffuse enhancement of
myocardium resulting in difficulty analyzing normal versus abnormal myocardium especially in
ATTR patients 37, b) missing patchy myocardial involvement and c) underappreciating disease
burden as compared to 99mTc-PYP 41. These limitations can be addressed by the use of new
advances, which includes visual T1 tissue enhancement, quantitative T1 mapping and phase
correction recovery LGE imaging technique.

T1 tissue enhancement is simply based on the concept of accumulation of contrast in the

extracellular space results in short inversion time (T1). This leads to delayed hyperenhancement
of extracellular space when compared to normal cardiac tissue. This hyperenhancement is
usually not limited to single coronary artery territory in amyloidosis. In suspected patients of
cardiac amyloidosis, it has found to have an impressive diagnostic and prognostic value 42.

Visual T1 mapping imaging is based on the concept of assessing images pre-and post-
gadolinium contrast and reconstructing images in the form to generate T1 maps of voxels
representing T1 relaxation time of the relative cardiac tissue. By comparing pre and post
contrast mapping, extracellular volume can be calculated 43. Short T1 time and large
extracellular volume represents the accumulation of amyloid fibrils in the extracellular matrix.
Recently, Benyaparsad et al found that in patients with AL amyloidosis, non-contrast T1
mapping demonstrated prolonged relaxation time in the cardiac tissue with a strong promise to
diagnose amyloidosis in subclinical stages as well as quantifying the severity of cardiac
involvement 44.

LGE when coupled with phase-sensitive inversion recovery has shown to provide a better
assessment of the extent of cardiac involvement. This evolving new technique overcomes the
limitations of T1 imaging by adjusting the signal intensities to accurate the wrong inversion
times. Recently, Fontana et al in patients with AL and ATTR classified patients in three
subcategories (normal, subendocardium and transmural) based on phase-sensitive inversion
recovery LGE images 45. Of these, transmural is associated with the worst prognosis, with a 5.4-
fold increase in mortality. They also formulated that progression of
normalsubendocardiumtransmural LGE reveals proportional relationship with extracellular
volume expansion 45. Altogether, CMR is an invaluable tool to establish the diagnosis of
amyloidosis.

Nuclear Imaging
Use of radiotracers has been used to diagnose amyloidosis. Most commonly, 99mTc-DPD
(technetium-3, 3-diphosphono-1, 2-propanodicarboxylic acid) and 99m Tc- PYP is used.

The exact mechanism by which these radiotracers accumulate in myocardium is not clear,
although various hypotheses have been proposed. Of these, one suggests that phosphate in the
radiotracers binds to high calcium level in the amyloidosis 46. Another hypotheses is based on
duration of amyloid deposition which occurs in less time frame in AL patients relative to more
indolent course of ATTR patients 47. As 99m Tc- PYP preferentially binds to ATTR relative to AL
fibrils, this technique also serves as a noninvasive way to distinguish the aforementioned
amyloidosis subtypes 47.
99m
Tc- DPD is not approved by the Federal Drug Administration in the US but has been mainly
used in Europe and was found to have high sensitivity for patients with ATTR. In two studies,
the specificity was found to be ranging from 70% 48 to 100% 49 to distinguish ATTR patients from
AL. On the other hand, 99m Tc- PYP is available in the US, which is used by Bokhari et al by
calculating heart to contralateral ratio score and found that ratio score >1.5 had excellent
sensitivity and specificity of 97% and 100%, respectively in differentiating ATTR and AL
amyloidosis 47. In this study, AL patients were also found to have radiotracer uptake but
calculating heart to contralateral ratio score can differentiate ATTR from AL. 99m Tc- PYP was
also used in a study by Yamamoto et al based on the concept of PYP score. It is calculated by
the ratio of myocardial mean count to the ventricular mean count and found to have a
sensitivity of close to 84% and specificity close to 94%, 50 differentiating cardiac amyloidosis
patients from other types.

Positron emission tomography (PET) offers higher spatial resolution than other nuclear imaging,
but it has sparse data as a diagnostic imaging in patients of amyloidosis. One of the studies
using tracer N [methyl-(11) C]2-(4-methylamino-phenyl)-6-hydroxybenzothiazole((11)C-PIB)
revealed that there was selective tracer uptake in ATTR and AL amyloidosis relative to healthier
volunteers 51. Most recently, a pilot study using 18F-florbetaben as a tracer found higher
percentage of tracer accumulation in amyloidosis patients as compared to hypertensive heart
disease patients, differentiating the two 52. The scope of PET imaging needs to be further
explored as a non-invasive diagnostic utility in amyloidosis. In conclusion, nuclear imaging
offers a diagnostic and prognostic value in amyloidosis particularly in ATTR patients.

Histopathological diagnosis
Besides all these modalities, biopsy with histopathology remains the gold standard showing
deposition of amorphous deposits of amyloid fibrils as shown in Figure 2. With advancement in
techniques, various methods have been evolved for the tissue diagnosis. Endomyocardial
biopsy (EMB) is a relatively safe procedure with sensitivity of almost 100% for diagnosing
amyloidosis 53. But it is not always necessary to perform EMB, as diagnosis can be suggested by
alternative tissues, such as abdominal fat, rectal tissue and other involved organs. Fine needle
aspiration is a simple, quick technique that have been used to diagnose amyloidosis with overall
positive results in 88% of cases 54, having a sensitivity of approximately 75% and specificity of
92% 55. If diagnosis remains unconfirmed even after biopsy of another tissue but index of
suspicion is high, EMB would be the next step and gold standard for the diagnosis 56.
The amyloid fibrils lead to characteristic apple green birefringence under polarized light
microscopy by binding to Congo red stain, as shown in Figure 3 and to Thioflavin producing an
intense yellow-green fluorescence. On electron microscopy they are straight, rigid and with
unbranching pattern along with 8-10mm width 57.

Figure 2- showing deposition of amorphous deposits of amyloid fibrils on tissue biopsy

Figure 3- Amyloid fibrils leads to characteristic apple green birefringence under polarized light
microscopy by binding to Congo red stain.
Diagnostic modalities Characteristic findings Early diagnostic Sensitivity and
finding Specificity
Echocardiography 1.Granular sparkling Abnormal
appearance relaxation of
ventricle 31
Strain imaging 2. Significant decrease
in longitudinal strain in Sensitivity and
the mid and basal wall specificity ranges
regions with relative from 90-95% and 80-
preservation of apical 85% respectively 35
region of longitudinal
strain 35
CMR LGE 37 Global transmural Sensitivity close to
or diffuse 80% and specificity of
subendocardial 94% 38
LGE 39

Visual T1 mapping Prolonged

imaging relaxation time in
the cardiac tissue
in AL amyloidosis
44
99m
Tc- PYP Heart to contralateral Sensitivity of 97%
ratio score >1.5 is and specificity of
significant in 100% 47
differentiating ATTR and
AL amyloidosis 47
Endomyocardial Deposition of Sensitivity close to
biopsy- Gold amorphous deposits of 100% 53
standard amyloid fibrils

Sensitivity of 75%
Fine needle Deposition of and specificity of 92%
55
aspiration of involved amorphous deposits of
organs amyloid fibrils

CMR- Cardiac magnetic resonance imaging, 99m Tc- PYP- Technetium pyrophosphate, LGE- Late
gadolinium enhancement, AL- Primary amyloidosis, ATTR- Familial amyloidosis

Table 2- Summarizes the characteristic findings, early diagnostic findings, sensitives and

specificity for various modalities for diagnosis of amyloidosis

Diagnostic approach in Cardiac amyloidosis

Figure 4- Showing diagnostic work up flow chart in suspicous cases of Amyloidosis

EKG- Electrocardiogram, BNP- Brain Natriuretic peptide, Echo- Echocardiography, CMR- Cardiac
Magnetic Resonance Imaging
Figure 5- Showing diagnostic flow chart for diagnosing individual Amyloidosis

AL-Primary amyloidosis, AA- Secondary amyloidosis, TTR- transthyretin, SSA- senile systemic
amyloidosis, 99Tc-PYP- Technetium pyrophosphate

Treatment of Amyloidosis
The prognosis of cardiac amyloidosis is poor in general, yet it depends on the type of
amyloidosis. Treatment can be divided into HF therapy, specific therapy for each amyloidosis,
along with organ transplantation, as well as future new novel agents currently under trials.
Heart Failure Therapy

Supportive therapy for HF includes the use of loop diuretics, which are the mainstay of the
treatment along with fluid and salt restriction. Often judicious use is required and maintaining
adequate fluid balance is difficult, as these patients are preload dependent. While Angiotensin
Converting Enzyme Inhibitors and Beta-Blockers (BBs) are the cornerstone of treatment for
other cardiomyopathies, they might be contraindicated in amyloid cardiomyopathy, as they
could worsen renal function or lead to postural hypotension. Calcium Channel Blockers are also
not helpful and can even worsen left ventricular function 58. Digoxin is generally avoided as it
can bind to amyloid fibrils causing toxicity 59 and should be used only if patient develops AF
with associated hypotension limiting the use of BBs. Along with pharmacotherapy, patient
education on HF is an important key for successful management. Recurrent or resistant pleural
effusion generally indicates involvement of pleura by amyloid infiltration and requires pleural
tap or pleurodesis 60. Anticoagulation with warfarin or other newer anticoagulants (dabigatran,
rivoroxaban, apixaban) is strongly recommended in patients with AF secondary to increase risk
of stroke unless contraindicated.

Pacemaker and Implantable Cardioverter-Defibrillator

Pacemakers are a reasonable option to consider for symptomatic therapy in patients with
advanced heart block. The role of prophylactic Implantable Cardioverter-Defibrillator (ICD)
remains indefinable in preventing SCD as electromechanical dissociation is the most common
cause of death. In a retrospective analysis of 53 patients (33 patients of AL ), out of which 41
underwent ICD implantation for primary prevention and 12 for secondary prevention, there
was no survival benefit of ICD implantation 61. Also, there was significant difference in terms of
ICD shocks with highest rate in AL amyloidosis and lower rate in ATTR and SSA. Similarly, other
study in Germany observed SCDs secondary to EMD even after ICD implantation 62. Better
approach for understanding of arrhythmia induced SCD attributable to amyloidosis is required.
Altogether, data on ICD implantation for primary prevention remains sparse with no survival
benefit.

Specific Therapy for Primary Amyloidosis

Chemotherapy is based on the concept of reducing number of amyloid fibrils and retarding the
disease process. In AL, chemotherapy and autologous hematopoietic stem cell transplant
(ASCT) is the mainstay of treatment. Chemotherapy in AL amyloidosis is aimed at reducing free
light chains. Bortezomib is a proteasome inhibitor that induces rapid hematological response
either alone or in combination with dexamethasone 22. Bortezomib along with dexamethasone
and cyclophosphamide is the first line treatment in these patients. Using Mayo staging as
stratification, an analysis of 230 patients treated with bortezomib, dexamethasone and
cyclophosphamide demonstrated better response and benefit in patients with stage I and II 63.
A matched case control study revealed higher hematological response of 42% to bortezomib
along with oral melphalan and dexamethasone as compared to 19% response to melphalan and
dexamethasone alone 64. Also, bortezomib and dexamethasone has shown to improve the
hematological response following ASCT in newly diagnosed AL patients 65. Standard dose
melphalan and dexamethasone has reported better survival outcomes in stage II patients when
compared to high risk stage III 66. Use of thalidomide has been shown to improve response to
therapy but also increases the risk of toxicities. It is usually better tolerated in lower dose in
combination with dexamethasone and cyclophosphamide 67. Patients with NT-pro BNP levels >
8500 ng/ml and systolic blood pressure <100 mm Hg are poor responders to chemotherapy and
have higher mortality rate 68.

Heart Transplantation
The role of orthotropic heart transplantation (OHT) in AL amyloidosis is still controversial and is
a challenging decision due to progressive disease course and recurrence of disease in the
transplanted heart 69, 70. Also, most of patients with AL amyloidosis have significant amyloidosis
load in other organ systems making them ineligible for OHT, which is more suitable for
candidates who have isolated cardiac amyloidosis. If performed, OHT should be followed by
chemotherapy and ASCT within a year. In 11 patients who received ASCT 6 months following
OHT, survival rate of 82% and 65% at 1 and 5 years, respectively was noted (two patients died
initially following complications of ASCT and three died subsequently between 55-66 months
interval due to progressive amyloidosis) 71. Similarly, another study at Massachusetts General
Hospital, Boston showed that sequential OHT and ASCT have demonstrated improved survival
rate on 4.6 year follow up with no evidence of recurrent amyloid disease in the grafts 72.In fact,
results are excellent with median survival of more than 10 years in patients who have
demonstrated complete hematological response and predominant heart involvement 73. In
general, younger patient <60years without associated plasma cell dyscrasias or other major
organ involvement are better candidates of to be considered for OHT.

Specific Therapy for Familial Amyloidosis

As mutant amyloid ATTR is produced in liver, orthotropic liver transplantation (OLT) is the
established treatment since 1990. Outcomes seem to be mutant dependent with favorable
outcomes in Val30Met mutation following OLT. In one study, 5-year survival rate was 100% vs
59% in Val30Met and non Val30Met patients 74. Retrospective analysis of world transplant
registry in patients of ATTR who underwent OLT demonstrated the survival rate of 55.3% along
with favorable outcomes in patients with Val30Met mutation as compared to non Val30Met
mutation at 20 year of follow up 75. Unfortunately, in patients with nonVal30Met mutation,
cardiac disease can still progress following OLT, which is attributed to deposition of native
TTRwt amyloid in the cardiac tissue similar to SSA 76, 77. Combined OHT and OLT is a viable
option for selected patients with good outcomes 78. Overall, neuropathy and organ dysfunction
continues to progress following OLT.
On the other hand, as an exception to above rule of combined OHT/OLT was reported in Val
122lle mutation, common in African American, in which no recurrent heart disease has been
reported even after 5 years of OHT 79.
TTR tetramer stabilizers (Tafamidis and Diflunisal) works by binding to TTR and stabilizing its
normal tetrameric structure preventing amyloid fibril formation 80, 81. Tafamidis is being used as
a pharmacological agent in Europe and Japan for treatment of ATTR. A non-randomized control
trail showed that it has not been able to halt the progression of neuropathy and morbidity in
Val30Met mutation patients 82. An international randomized, double-blind, placebo-controlled
study demonstrated diflunisal (non-steroidal anti-inflammatory drug) has reduced the
progression rate of polyneuropathy in ATTR patients 83.

Specific Therapy for Senile Cardiac Amyloidosis

Patients with HF secondary to SSA are treated symptomatically on presentation. In future,
drugs such as tafamidis and diflunisal, currently be studied in clinical trials, could have role in
treatment of SSA 11. Although patients with SSA usually have isolated involvement of the heart,
consideration of life expectancy along with other comorbidities should be undertaken because
of late presentation in seventh or eighth decade. Cases have been reported at earlier age and
successful OHT 84.

Future Directions
The evolving newer novel agents currently under trials are summarized in Table 3. Besides
these, another agent, Curcumin, with antioxidant and anti-inflammatory properties, has shown
promising results in decreasing TTR deposition in tissue and tissue toxicity in mice models and
could serve as an therapeutic agent for advanced stage transthyretin amyloidosis 85.
Furthermore, surprisingly, an observational study in Germany reported reductions in amyloid
burden and left ventricular mass on one year follow up in patients using green tea extract 86.
These emerging newer therapeutic agents may be able to revolutionize the treatment of
amyloidosis in future.
New novel agents Trial Number Trail Mechanism of action Type of
phase Amyloidosis
Pomalidomide and NCT01510613 II Antiangiogenic and AL
dexamethasone immunomodulatory
Ixazomib and NCT01659658, III Proteasome Relapsed or
Carfilzomib NCT01789242 I inhibitors treatment
resistant AL
amyloidosis
Tafamidis 80, 81 NCT01994889 III Binds to TTR and ATTR
stabilizing its normal
tetrameric structure
preventing amyloid
fibril formation
siRNA lipid Anti-transthyretin ATTR
nanoparticles ALN- small interfering
TTR01, NCT01148953 I ribonucleic acid
ALN-TTR020 87 NCT01559077 I (siRNA) lipid
Patisiran (ALN- nanoparticles focus
TTR02) NCT01961921 II on reducing the
and production mutant
Revusiran (ALN- and non-mutant
TTRsc) NCT02319005 III forms of
transthyretin
ISIS-TTRRx 88 NCT01737398 III Works on the ATTR
principle of antisense
oligonucleotide and
knocks down both
mutant and non-
mutant form of
transthyretin.
Doxycycline and NCT01171859 II Suppresses the TTR ATTR
tauroursodeoxycholic amyloid deposit in
acid 89 transgenic
Val30EMet mutation
GSK3039294 NCT02603172 I Monoclonal AL
antibodies targeting
Serum amyloid P
component (anti-
SAP)
AL-Primary amyloidosis, AA- Secondary amyloidosis, ATTR-Familial amyloidosis

Table 3- Summarizing evolving newer novel agents currently under trials

Conclusion
Cardiac amyloidosis is a life-threatening disease in which myocardial involvement is the main
driver of prognosis of systemic amyloidosis, so stratification of patients is essential for
prognosis and accurate medical or surgical management. Although no single pathognomonic
test is available to diagnose amyloidosis, noninvasive tests, including low voltage ECG coupled
with echo findings of LVH and/or DD in the absence of hypertension could be strongly
suggestive of early lead in the diagnosis. CMR with LGE and phase-sensitive inversion recovery
is valuable in finding the disease in its early phase. It is important to diagnose the individual
cardiac amyloidosis as treatment options vary. In general, supportive therapy for HF,
chemotherapy, ASCT and organ transplant (OHT/OLT) are the currently available options for
treatment, while the newer therapies are being studied with the anticipation of making the
prognosis better in the future. Even with recent advances in the treatment, the overall
prognosis remains overall quite dismal. In suspected cases, clinicians should have a high index
of suspicion and low threshold to use available diagnostic techniques for early diagnosis, as it
could be of paramount importance in improving the potential survival outcomes.

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