Cardiac Amyloidosis

NAME: SALAM MAJZOUB

PRECEPTOR: DR. LAMA FADDOUL

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 Outline
• Overview of Cardiac Amyloidosis:
–Epidemiology
–Amyloidogenic cascade
• Clinical Features
• Clinical Presentations
• Diagnosing Cardiac Amyloidosis :
─Tissue biopsy, blood / urine tests, imaging
─Diagnostic algorithm
• Managing Cardiac Amyloidosis :
–Non-disease modifying therapies for HF symptoms
–Targeted therapies for ATTR-CM Outline

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Overview of Cardiac
Amyloidosis

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 What is Amyloidosis?
• Amyloidosis is a disorder of protein folding
• The protein misfolding abnormalities result in amyloid fibrils and may manifest as:
1) Primary
2) Secondary
3) Familial
4) Senile
amyloidosis

• amyloid fibrils deposit in organs resulting in organ dysfunction and can occur in multiple organs
(heart, liver, kidney, skin, eyes, lungs, nervous system) resulting in a variety of clinical manifestations

• Cardiac amyloidosis: a disorder caused by amyloid fibril deposition in the extracellular space of the heart

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 Cardiac involvement
• A progressive disorder resulting in early death due to:
1. congestive heart failure
2. Arrhythmias
• can occur as part of a systemic disease or as a localized phenomenon
• Pathophysiology:
o May be a result of genetic mutations or excess formation
o Is insoluble
o Amyloid deposition in the tissues causes disruption of architecture, induces oxidant
stress, and results in organ dysfunction
o Multiorgan involvement is common
o Cardiac involvement is most common in the AL variety but is also seen in secondary,
hereditary, and senile amyloidosis

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 Various types of amyloid
most common
type of systemic
amyloidosis

are the two

major types
of amyloid

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AL Amyloidosis

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Prevalence

AL type is more
prevalent in males than
in females

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ATTR Amyloidosis

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Prevalence

ATTR Amyloidosis is more prevalent

in elderly population, In A.A, and to
a lesser degree in Irish population

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Clinical features

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Clinical features varies with amyloid type

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 Transthyretin Amyloid Cardiomyopathy

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 Amyloid Cardiomyopathy
1. Clinical history / Physical exam:
• Exclusive cardiac involvement is exception, not rule in AL- and ATTR types
• Diagnosis can be delayed months - years
• However, absence of extra-cardiac findings can be misleading :
–macroglossia, periorbital purpura (rare, but very specific for AL)
– Diagnostic ‘red flags’ in patients with LVH:
• Carpal tunnel syndrome (ATTR), particularly bilateral in males
• Spinal stenosis in males /‘carpal tunnel’ of the back
• Hx of unexplained neuropathic pain, orthostatic
hypotension, and ‘HCM’ after age 60

• High index of suspicion in patients with HFpEF in the absence of hypertension or ischemia

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 Amyloid Cardiomyopathy
2. Laboratory tests:

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Clinical presentations

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 Clinical presentations
Age of onset of symptoms and disease distribution varies among the various types of amyloidosis

 Patients with (AL) cardiac amyloidosis typically present at age ≥40 years
 Systemic AL amyloidosis is a multisystem disorder which commonly affects the liver, kidneys,
spleen, the autonomic and peripheral nervous systems, lungs, and heart
 Cardiac amyloid infiltration is present in most patients with AL amyloidosis (50 to 70 percent) and
it is the main determinant of prognosis


 Patients with ATTR cardiac amyloidosis typically present at age ≥60 years, and most commonly >70
years
 Cardiac amyloidosis is the dominant feature of ATTRwt and for some ATTR variants

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 Clinical presentations
• Lower extremity edema
• Elevated jugular venous pressure which are caused by restrictive
cardiomyopathy with
• Hepatic congestion
predominantly right ventricular
• Ascites failure
• Dyspnea
• symptoms and signs of low cardiac output are features of advanced disease
• Angina is uncommon, although microvascular dysfunction is a frequent finding
• Amyloidogenic light chains may be toxic to myocardial cells as suggested by in vitro studies
• clinical observation suggest worse symptoms in patients with AL amyloidosis compared with patients with
ATTR amyloidosis with similar degrees of cardiac involvement

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 Syncope in cardiac amyloidosis
• Patients present with syncope or presyncope:

Frequently caused by bradyarrhythmias or

advanced AV block
Infrequently caused by ventricular arrhythmia

• Other conditions such as postural or exertional

hypotension caused by excessive diuresis or
autonomic neuropathy may also contribute

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ATTR-CM is not uncommon
So it’s not very
uncommon in HF AND
aortic stenosis patients

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Diagnosis

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First: second:

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third: Do an Echo

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• Tc99m-PYP Scanning:

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• Non-biopsy diagnosis of ATTR-CM:

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 Screening for cardiac amyloidosis
summary
1. ECG: absence of low voltage does not exclude amyloid
2. Echo, MRI: crucial but do not subtype amyloid
3. Immuno-electrophoresis (serum, urine), free light chains – AL
4. Fat aspirate: Don’t stop if negative
5. Nuclear PYP scanning: sensitive and specific for TTR
6. Remaining clinical suspicion – EMB
7. NT- proBNP and Troponin levels: prognostic utility in AL and ATTR

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Management

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Staging: AL amyloidosis
changes in NT-proBNP have also been used to predict response to treatment and
disease progression

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 Staging: ATTR amyloidosis 
Two staging systems:

Staging system The first The second

Used for ATTRwt ATTRwt and ATTRm

Based on serum levels of: serum levels of:

• NT- proBNP • NT- proBNP
• cardiac troponin T • Estimated glomerular filtration rate (e GFR)

Threshold used • troponin T (0.05 Stage I : 69.2 months

ng/ml) • NT-proBNP ≤3000 ng/L
• NT-proBNP (3000 • eGFR ≥45 mL/min
pg/ml)
Stage 1: 57% survival Stage III : 24.1 months
Stage 2: 42% • NT-proBNP >3000 ng/L
Stage 3: 18% • eGFR <45 mL/min
the remainder were Stage II: 46.7 months

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 General considerations
Treatment is 2
folds

therapy for
therapy for HF
underlying disease

ATTRm or ATTRwt amyloidosis AL amyloidosis

• generally respond better to HF therapy • there are more therapeutic options
for addressing the underlying disease
in AL amyloidosis
• rapid decrease in serum biomarkers of
HF if the plasma cell dyscrasia is
controlled

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Treatment of heart
failure

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 Treatment of heart failure
• It differs from the therapy generally recommended

• Digoxin:
_Amyloid fibrils bind to digoxin and this interaction may account for increased susceptibility to digitalis
toxicity
_Relatively contraindicated
_careful use of digoxin may be of value in a patient with atrial fibrillation and a rapid ventricular response,
particularly when hypotension makes beta blocker unatenable

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Medical therapy

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Heart transplantation and ventricular
assist devices

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 Atrial fibrillation 
Medication Comments

Low-dose BBs Use may help with rate control

Digoxin Use may help with rate control

Amiodarone  Use to maintain sinus rhythm appears to be well tolerated

Catheter ablation • Experience is limited
• symptomatic improvement but without evidence of change in
disease-related mortality

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Anticoagulation

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 Other considerations
Conduction disease  Implantable cardioverter-defibrillator 
• Patients with amyloid cardiomyopathy • prophylactic ICDs have been suggested
are at risk of conduction system disease as an option to reduce risk of sudden
• general indications for cardiac pacing cardiac death
should be applied •  The efficacy is uncertain

• the available clinical data do not support

use
• ICD should be considered In the patient
who is resuscitated from a life-
threatening ventricular arrhythmia

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 Treatment of the
underlying protein
misfolding disorder
VARIES WITH THE CAUSE OF EXCESS FIBRIL PRODUCTION

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Specific therapy for AL amyloidosis
Treating AL amyloidosis
survival • varies with the extent of organ involvement
• The median survival is as short as four to six months in
those with HF  
• survival can be significantly prolonged with:
earlier diagnosis, careful patient selection, and use of
currently available chemotherapeutic regimens

Therapy involves Administration of:

⁻ Chemotherapy
⁻ Autologous stem cell transplantation (ASCT)
in an attempt to treat the underlying plasma cell clone
responsible for AL amyloid formation

Goal of therapy to achieve a min of 90% reduction in serum free AL

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Specific therapy for AL amyloidosis

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Specific therapy for ATTR amyloidosis
ATTR cardiomyopathy Treatment comments
NYHA functional class I to III tafamidis • Reduces mortality
• Reduces cardiovascular-
related hospitalizations
• Reduced declines in
functional capacity and
quality of life

patients diagnosed with liver transplantation • can be curative

ATTRm cardiomyopathy not
ATTRwt

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 Based on The multicentre randomized
ATTR-ACT trial:
therapy Tafamidis Liver transplantation
MOA • stabilizes the transthyretin • Transplantation of the liver removes the
tetramer and may thus reduce mutant amyloidogenic in ATTRm, but not in
formation of TTR amyloid ATTRwt
Dose(FDA approved ) • 80 mg qd (Vyndaqel) • Patients with advanced heart disease(HF)
• 61 mg qd (Vyndamax) may be treated with combined heart and
liver transplantation or just heart alone
effectiveness • Effective • Unfortunately, cardiac disease has
progressed after liver transplantation in
some patients with familial ATTR
Adverse events The incidence of adverse events
was similar in the tafamidis and
placebo groups

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Investigational agents

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 Final thoughts

For ATTR amyloidosis,

The paradigm of Definitive diagnosis patients should be
cardiac amyloidosis Greater numbers of Marked requires biopsy and is referred for
has changed patients are improvements in crucial for definitively evaluation for
markedly in the last diagnosed therapeutic options subtyping the enrollment in one of
decade amyloid deposits the ongoing clinical
trials

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 References
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Thank you!

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